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Discovery of small molecule degraders for modulating cell cycle

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Abstract

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

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References

  1. Malumbres M. Cyclin-dependent kinases. Genome Biol 2013; 12(6): 122

    Google Scholar 

  2. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2002; 30(11): 630–631

    Google Scholar 

  3. Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol 2022; 23(1): 73–88

    Google Scholar 

  4. Lee MG, Nurse P. Cell cycle genes of the fission yeast. Sci Prog 1987;71:1–13

    CAS  PubMed  Google Scholar 

  5. Russell P, Nurse P. Schizosaccharomyces pombe and Saccharomyces cerevisiae: a look at yeasts divided. Cell 1986; 32(6): 781–782

    Google Scholar 

  6. Elledge SJ, Spottswood MR. A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Eg1. EMBO J 1991; 10(9): 2653–2659

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 1992; 71(2): 323–334

    CAS  PubMed  Google Scholar 

  8. Xiong Y, Zhang H, Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 1992; 71(3): 505–514

    CAS  PubMed  Google Scholar 

  9. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A. Structure and regulation of the CDK5-p25(nck5a) complex. Mol Cell 2001; 8(3): 657–669

    CAS  PubMed  Google Scholar 

  10. Łukasik P, Zaluski M, Gutowska I. Cyclin-dependent kinases (CDK) and their role in diseases development-review. Int J Mol Sci 2021; 22(6): 2935

    PubMed  PubMed Central  Google Scholar 

  11. Whittaker SR, Mallinger A, Workman P, Clarke PA. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther 2017; 173: 83–105

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013; 140(15): 3079–3093

    CAS  PubMed  Google Scholar 

  13. Filippone MG, Gaglio D, Bonfanti R, Tucci FA, Ceccacci E, Pennisi R, Bonanomi M, Jodice G, Tillhon M, Montani F, Bertalot G, Freddi S, Vecchi M, Taglialatela A, Romanenghi M, Romeo F, Bianco N, Munzone E, Sanguedolce F, Vago G, Viale G, Di Fiore PP, Minucci S, Alberghina L, Colleoni M, Veronesi P, Tosoni D, Pece S. CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer. Nat Commun 2022; 13(1): 2642

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hamilton MJ, Suri M. CDK13-related disorder. Adv Genet 2019; 103: 163–182

    CAS  PubMed  Google Scholar 

  15. Liu W, Zhou Y, Liang R, Zhang Y. Inhibition of cyclin-dependent kinase 5 activity alleviates diabetes-related cognitive deficits. FASEB J 2019; 33(12): 14506–14515

    CAS  PubMed  Google Scholar 

  16. Shelton SB, Johnson GV. Cyclin-dependent kinase-5 in neurodegeneration. J Neurochem 2004; 88(6): 1313–1326

    CAS  PubMed  Google Scholar 

  17. Xie Z, Hou S, Yang X, Duan Y, Han J, Wang Q, Liao C. Lessons learned from past cyclin-dependent kinase drug discovery efforts. J Med Chem 2022; 65(9): 6356–6389

    CAS  PubMed  Google Scholar 

  18. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16(1): 25–35

    CAS  PubMed  Google Scholar 

  19. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, Andre F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O’Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375(18): 1738–1748

    CAS  PubMed  Google Scholar 

  20. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015; 14(2): 130–146

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Peyressatre M, Prevel C, Pellerano M, Morris MC. Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers (Basel) 2015; 7(1): 179–237

    CAS  PubMed  Google Scholar 

  22. Tadesse S, Caldon EC, Tilley W, Wang S. Cyclin-dependent kinase 2 inhibitors in cancer therapy: an update. J Med Chem 2019; 62(9): 4233–4251

    CAS  PubMed  Google Scholar 

  23. Cao C, He M, Wang L, He Y, Rao Y. Chemistries of bifunctional PROTAC degraders. Chem Soc Rev 2022; 51(16): 7066–7114

    CAS  PubMed  Google Scholar 

  24. Dong G, Ding Y, He S, Sheng C. Molecular glues for targeted protein degradation: from serendipity to rational discovery. J Med Chem 2021; 64(15): 10606–10620

    CAS  PubMed  Google Scholar 

  25. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 2022; 21(3): 181–200

    PubMed  PubMed Central  Google Scholar 

  26. Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, Tong Y, Rao Y. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther 2019; 4(1): 64

    PubMed  PubMed Central  Google Scholar 

  27. Weng G, Cai X, Cao D, Du H, Shen C, Deng Y, He Q, Yang B, Li D, Hou T. PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Res 2023; 51(D1): D1367–D1372

    PubMed  Google Scholar 

  28. Zhou X, Dong R, Zhang JY, Zheng X, Sun LP. PROTAC: a promising technology for cancer treatment. Eur J Med Chem 2020; 203: 112539

    CAS  PubMed  Google Scholar 

  29. Wang Y, Jiang X, Feng F, Liu W, Sun H. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B 2020; 10(2): 207–238

    CAS  PubMed  Google Scholar 

  30. Rana S, Mallareddy JR, Singh S, Boghean L, Natarajan A. Inhibitors, PROTACs and molecular glues as diverse therapeutic modalities to target cyclin-dependent kinase. Cancers (Basel) 2021; 13(21): 5506

    CAS  PubMed  Google Scholar 

  31. Zhou F, Chen L, Cao C, Yu J, Luo X, Zhou P, Zhao L, Du W, Cheng J, Xie Y, Chen Y. Development of selective mono or dual PROTAC degrader probe of CDK isoforms. Eur J Med Chem 2020; 187: 111952

    CAS  PubMed  Google Scholar 

  32. Teng M, Jiang J, He Z, Kwiatkowski NP, Donovan KA, Mills CE, Victor C, Hatcher JM, Fischer ES, Sorger PK, Zhang T, Gray NS. Development of CDK2 and CDK5 dual degrader TMX-2172. Angew Chem Int Ed 2020; 59(33): 13865–13870

    CAS  Google Scholar 

  33. Wei M, Zhao R, Cao Y, Wei Y, Li M, Dong Z, Liu Y, Ruan H, Li Y, Cao S, Tang Z, Zhou Y, Song W, Wang Y, Wang J, Yang G, Yang C. First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo. Eur J Med Chem 2021; 209: 112903

    CAS  PubMed  Google Scholar 

  34. Wang L, Shao X, Zhong T, Wu Y, Xu A, Sun X, Gao H, Liu Y, Lan T, Tong Y, Tao X, Du W, Wang W, Chen Y, Li T, Meng X, Deng H, Yang B, He Q, Ying M, Rao Y. Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy. Nat Chem Biol 2021; 17(5): 567–575

    CAS  PubMed  Google Scholar 

  35. Hati S, Zallocchi M, Hazlitt R, Li Y, Vijayakumar S, Min J, Rankovic Z, Lovas S, Zuo J. AZD5438-PROTAC: a selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss. Eur J Med Chem 2021; 226: 113849

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao B, Burgess K. PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer. Chem Commun (Camb) 2019; 55(18): 2704–2707

    CAS  PubMed  Google Scholar 

  37. Jiang B, Wang ES, Donovan KA, Liang Y, Fischer ES, Zhang T, Gray NS. Development of dual and selective degraders of cyclin-dependent kinases 3 and 6. Angew Chem 2019; 131(19): 6387–6392

    Google Scholar 

  38. Su S, Yang Z, Gao H, Yang H, Zhu S, An Z, Wang J, Li Q, Chandarlapaty S, Deng H, Wu W, Rao Y. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders. J Med Chem 2019; 62(16): 7272–7282

    Google Scholar 

  39. Rana S, Bendjennat M, Kour S, King HM, Kizhake S, Zahid M, Natarajan A. Selective degradation of CDK6 by a palbociclib based PROTAC. Bioorg Med Chem Lett 2019; 29(11): 1372–1379

    Google Scholar 

  40. Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB. Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs. Bioorg Med Chem Lett 2020; 30(9): 127106

    CAS  PubMed  Google Scholar 

  41. Steinebach C, Ng YLD, Sosic I, Lee CS, Chen S, Lindner S, Vu LP, Bricelj A, Haschemi R, Monschke M, Steinwarz E, Wagner KG, Bendas G, Luo J, Gutschow M, Kronke J. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem Sci (Camb) 2020; 11(13): 3373–3386

    Google Scholar 

  42. De Dominici M, Porazzi P, Xiao Y, Chao A, Tang HY, Kumar G, Fortina P, Spinelli O, Rambaldi A, Peterson LF, Petruk S, Barletta C, Mazo A, Cingolani G, Salvino JM, Calabretta B. Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs. Blood 2020; 132(18): 1260–1273

    Google Scholar 

  43. Pu C, Liu Y, Deng R, Xu Q, Wang S, Zhang H, Luo D, Ma X, Tong Y, Li R. Development of PROTAC degrader probe of CDK3/6 based on DCAF16. Bioorg Chem 2023; 138: 106637

    CAS  PubMed  Google Scholar 

  44. Xiong Y, Zhong Y, Yim H, Yang X, Park KS, Xie L, Poulikakos PI, Han X, Xiong Y, Chen X, Liu J, Jin J. Bridged proteolysis targeting chimera (PROTAC) enables degradation of undruggable targets. J Am Chem Soc 2022; 133(39): 22622–22632

    Google Scholar 

  45. Verano AL, You I, Donovan KA, Mageed N, Yue H, Nowak RP, Fischer ES, Wang ES, Gray NS. Redirecting the neo-substrate specificity of cereblon-targeting PROTACs to Helios. ACS Chem Biol 2022; 17(9): 2303–2310

    Google Scholar 

  46. Hatcher JM, Wang ES, Johannessen L, Kwiatkowski N, Sim T, Gray NS. Development of highly potent and selective steroidal inhibitors and degraders of CDK8. ACS Med Chem Lett 2018; 9(6): 230–232

    Google Scholar 

  47. Robb CM, Contreras JI, Kour S, Taylor MA, Abid M, Sonawane YA, Zahid M, Murry DJ, Natarajan A, Rana S. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun (Camb) 2017; 23(23): 7277–7280

    Google Scholar 

  48. King HM, Rana S, Kubica SP, Mallareddy JR, Kizhake S, Ezell EL, Zahid M, Naldrett MJ, Alvarez S, Law HC, Woods NT, Natarajan A. Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax. Bioorg Med Chem Lett 2021; 33: 128061

    Google Scholar 

  49. Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, Zhang T, Kwiatkowski N, Boukhali M, Green JL, Haas W, Nomanbhoy T, Fischer ES, Young RA, Bradner JE, Winter GE, Gray NS. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat Chem Biol 2018; 13(2): 163–170

    Google Scholar 

  50. Bian J, Ren J, Li Y, Wang J, Xu X, Feng Y, Tang H, Wang Y, Li Z. Discovery of wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity. Bioorg Chem 2018; 81: 373–381

    CAS  PubMed  Google Scholar 

  51. Qiu X, Li Y, Yu B, Ren J, Huang H, Wang M, Ding H, Li Z, Wang J, Bian J. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion. Eur J Med Chem 2021; 211: 113091

    CAS  PubMed  Google Scholar 

  52. Wei D, Wang H, Zeng Q, Wang W, Hao B, Feng X, Wang P, Song N, Kan W, Huang G, Zhou X, Tan M, Zhou Y, Huang R, Li J, Chen XH. Discovery of potent and selective CDK9 degraders for targeting transcription regulation in triple-negative breast cancer. J Med Chem 2021; 63(19): 13822–13837

    Google Scholar 

  53. Ao M, Wu J, Cao Y, He Y, Zhang Y, Gao X, Xue Y, Fang M, Wu Z. The synthesis of PROTAC molecule and new target KAT6A identification of CDK9 inhibitor iCDK9. Chin Chem Lett 2023; 33(3): 107731

    Google Scholar 

  54. Li J, Liu T, Song Y, Wang M, Liu L, Zhu H, Li Q, Lin J, Jiang H, Chen K, Zhao K, Wang M, Zhou H, Lin H, Luo C. Discovery of small-molecule degraders of the CDK9-cyclin T1 complex for targeting transcriptional addiction in prostate cancer. J Med Chem 2022; 62(16): 11033–11027

    Google Scholar 

  55. Tokarski RJ2nd, Sharpe CM, Huntsman AC, Mize BK, Ayinde OR, Stahl EH, Lerma JR, Reed A, Carmichael B, Muthusamy N, Byrd JC, Fuchs JR. Bifunctional degraders of cyclin dependent kinase 9 (CDK9): probing the relationship between linker length, properties, and selective protein degradation. Eur J Med Chem 2023; 223: 112332

    Google Scholar 

  56. Pei J, Xiao Y, Liu X, Hu W, Sobh A, Yuan Y, Zhou S, Hua N, Mackintosh SG, Zhang X, Basso KB, Kamat M, Yang Q, Licht JD, Zheng G, Zhou D, Lv D. Piperlongumine conjugates induce targeted protein degradation. Cell Chem Biol 2023; 30(2): 203–213.e17

    CAS  PubMed  Google Scholar 

  57. Jiang B, Gao Y, Che J, Lu W, Kaltheuner IH, Dries R, Kalocsay M, Berberich MJ, Jiang J, You I, Kwiatkowski N, Riching KM, Daniels DL, Sorger PK, Geyer M, Zhang T, Gray NS. Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol 2021; 17(6): 672–683

    Google Scholar 

  58. Niu T, Li K, Jiang L, Zhou Z, Hong J, Chen X, Dong X, He Q, Cao J, Yang B, Zhu CL. Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-cyclin K complex and induce synthetic lethality with PARP inhibitor. Eur J Med Chem 2022; 228: 113012

    Google Scholar 

  59. Yang J, Chang Y, Tien JC, Wang Z, Zhou Y, Zhang P, Huang W, Vo J, Apel IJ, Wang C, Zeng VZ, Cheng Y, Li S, Wang GX, Chinnaiyan AM, Ding K. Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13. J Med Chem 2022; 62(16): 11066–11083

    Google Scholar 

  60. Huang HT, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, Buckley DL, Cho JH, Ko E, Jang J, Shi K, Choi HG, Griffin JD, Li Y, Treon SP, Fischer ES, Bradner JE, Tan L, Gray NS. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol 2018; 22(1): 88–99.e6

    Google Scholar 

  61. Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Frohling S, Golub TR, Fischer ES, Thoma NH, Ebert BL. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 2020; 282(7823): 293–297

    Google Scholar 

  62. Lv L, Chen P, Cao L, Li Y, Zeng Z, Cui Y, Wu Q, Li J, Wang JH, Dong MQ, Qi X, Han T. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 2020; 9: e29993

    Google Scholar 

  63. Mayor-Ruiz C, Bauer S, Brand M, Kozicka Z, Siklos M, Imrichova H, Kaltheuner IH, Hahn E, Seiler K, Koren A, Petzold G, Fellner M, Bock C, Muller AC, Zuber J, Geyer M, Thoma NH, Kubicek S, Winter GE. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat Chem Biol 2020; 16(11): 1199–1207

    CAS  PubMed  PubMed Central  Google Scholar 

  64. McCurdy SR, Pacal M, Ahmad M, Bremner RA. CDK2 activity signature predicts outcome in CDK2-low cancers. Oncogene 2017; 36(18): 2391–2202

    Google Scholar 

  65. Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. eLife 2013; 3: e02872

    Google Scholar 

  66. Martín A, Odajima J, Hunt SL, Dubus P, Ortega S, Malumbres M, Barbacid M. Cdk2 is dispensable for cell cycle inhibition and tumor suppression mediated by p27(Kip1) and p21(Cip1). Cancer Cell 2002; 7(6): 291–298

    Google Scholar 

  67. Bashir T, Pagano M. Cdk1: the dominant sibling of Cdk2. Nat Cell Biol 2002; 7(8): 779–781

    Google Scholar 

  68. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P. Cdk2 knockout mice are viable. Curr Biol 2003; 13(20): 1772–1782

    Google Scholar 

  69. Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, Wang S. Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discov Today 2020; 22(2): 306–313

    Google Scholar 

  70. Ying M, Shao X, Jing H, Liu Y, Qi X, Cao J, Chen Y, Xiang S, Song H, Hu R, Wei G, Yang B, He Q. Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2. Blood 2018; 131(23): 2698–2711

    CAS  PubMed  Google Scholar 

  71. Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G, Schneckenleithner C, Salazar-Roa M, Zöchbauer-Müller S, Zuber J, Malumbres M, Kollmann K, Sexl V. CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 2012; 122(1): 90–101

    Google Scholar 

  72. Maurer B, Brandstoetter T, Kollmann S, Sexl V, Prchal-Murphy M. Inducible deletion of CDK3 and CDK6—deciphering CDK3/6 inhibitor effects in the hematopoietic system. Haematologica 2021; 106(10): 2623–2632

    Google Scholar 

  73. Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl) 2016; 93(12): 1313–1326

    Google Scholar 

  74. Bisteau X, Paternot S, Colleoni B, Ecker K, Coulonval K, De Groote P, Declercq W, Hengst L, Roger PP. CDK3 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK3/CDK2 interplay mediated by p21 phosphorylation at the restriction point. PLoS Genet 2013; 9(2): e1003236

    Google Scholar 

  75. Goel S, Bergholz JS, Zhao JJ. Targeting CDK3 and CDK6 in cancer. Nat Rev Cancer 2022; 22(6): 326–372

    Google Scholar 

  76. Wagner V, Gil J. Senescence as a therapeutically relevant response to CDK3/6 inhibitors. Oncogene 2020; 39(29): 2162–2176

    Google Scholar 

  77. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK3/6 inhibitors. Nat Rev Clin Oncol 2016; 13(7): 317–330

    Google Scholar 

  78. Bockstaele L, Bisteau X, Paternot S, Roger PP. Differential regulation of cyclin-dependent kinase 3 (CDK3) and CDK6, evidence that CDK3 might not be activated by CDK7, and design of a CDK6 activating mutation. Mol Cell Biol 2009; 29(12): 3188–3200

    Google Scholar 

  79. Dai M, Boudreault J, Wang N, Poulet S, Daliah G, Yan G, Moamer A, Burgos SA, Sabri S, Ali S, Lebrun JJ. Differential regulation of cancer progression by CDK3/6 plays a central role in DNA replication and repair pathways. Cancer Res 2021; 81(2): 1332–1336

    CAS  PubMed  Google Scholar 

  80. Puyol M, Martín A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaría D, Barbacid M. A Synthetic lethal interaction between K-Ras oncogenes and Cdk3 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 2010; 18(1): 63–73

    CAS  PubMed  Google Scholar 

  81. Honma T, Yoshizumi T, Hashimoto N, Hayashi K, Kawanishi N, Fukasawa K, Takaki T, Ikeura C, Ikuta M, Suzuki-Takahashi I, Hayama T, Nishimura S, Morishima H. A novel approach for the development of selective Cdk3 inhibitors: library design based on locations of Cdk3 specific amino acid residues. J Med Chem 2001; 33(26): 3628–3630

    Google Scholar 

  82. Ng YLD, Ramberger E, Bohl SR, Dolnik A, Steinebach C, Conrad T, Muller S, Popp O, Kull M, Haji M, Gutschow M, Dohner H, Walther W, Keller U, Bullinger L, Mertins P, Kronke J. Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma. Nat Commun 2022; 13(1): 1009

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Du G, Jiang J, Henning NJ, Safaee N, Koide E, Nowak RP, Donovan KA, Yoon H, You I, Yue H, Eleuteri NA, He Z, Li Z, Huang HT, Che J, Nabet B, Zhang T, Fischer ES, Gray NS. Exploring the target scope of KEAP1 E3 ligase-based PROTACs. Cell Chem Biol 2022; 29(10): 1370–1381.e31

    Google Scholar 

  84. Dhavan R, Tsai LH. A decade of CDK2. Nat Rev Mol Cell Biol 2001; 2(10): 739–729

    Google Scholar 

  85. Pao PC, Tsai LH. Three decades of Cdk2. J Biomed Sci 2021; 28(1): 79

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang J, Herrup K. Cdk2 and the non-catalytic arrest of the neuronal cell cycle. Cell Cycle 2008; 7(22): 3387–3390

    Google Scholar 

  87. Mangold N, Pippin J, Unnersjoe-Jess D, Koehler S, Shankland S, Brahler S, Schermer B, Benzing T, Brinkkoetter PT, Hagmann H. The atypical cyclin-dependent kinase 2 (Cdk2) guards podocytes from apoptosis in glomerular disease while being dispensable for podocyte development. Cells 2021; 10(9): 2363

    Google Scholar 

  88. Ao C, Li C, Chen J, Tan J, Zeng L. The role of Cdk2 in neurological disorders. Front Cell Neurosci 2022; 16: 921202

    Google Scholar 

  89. Lenjisa JL, Tadesse S, Khair NZ, Kumarasiri M, Yu M, Albrecht H, Milne R, Wang S. CDK2 in oncology: recent advances and future prospects. Future Med Chem 2017; 9(16): 1939–1962

    CAS  PubMed  Google Scholar 

  90. Takahashi S, Ohshima T, Hirasawa M, Pareek TK, Bugge TH, Morozov A, Fujieda K, Brady RO, Kulkarni AB. Conditional deletion of neuronal cyclin-dependent kinase 2 in developing forebrain results in microglial activation and neurodegeneration. Am J Pathol 2010; 176(1): 320–329

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Daniels MH, Malojcic G, Clugston SL, Williams B, Coeffet-Le Gal M, Pan-Zhou XR, Venkatachalan S, Harmange JC, Ledeboer M. Discovery and optimization of highly selective inhibitors of CDK2. J Med Chem 2022; 62(3): 3272–3296

    Google Scholar 

  92. Galbraith MD, Donner AJ, Espinosa JM. CDK8: a positive regulator of transcription. Transcription 2010; 1(1): 3–12

    Google Scholar 

  93. Belakavadi M, Fondell JD. Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol Cell Biol 2010; 30(10): 2437–2448

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Donner AJ, Ebmeier CC, Taatjes DJ, Espinosa JM. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol 2010; 17(2): 194–201

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Szilagyi Z, Gustafsson CM. Emerging roles of Cdk8 in cell cycle control. Biochim Biophys Acta Gene Regul Mech 2013; 1829(9): 916–920

    CAS  Google Scholar 

  96. Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dolken L, Strobl B, Muller M, Taatjes DJ, Kovarik P. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 2013; 38(2): 250–262

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Serrao A, Jenkins LM, Chumanevich AA, Horst B, Liang J, Gatza ML, Lee NY, Roninson IB, Broude EV, Mythreye K. Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer. Oncogene 2018; 37(35): 4792–4808

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Fryer CJ, White JB, Jones KA. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 2004; 16(4): 509–520

    CAS  PubMed  Google Scholar 

  99. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 2008; 455(7212): 547–551

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Liang J, Chen M, Hughes D, Chumanevich AA, Altilia S, Kaza V, Lim CU, Kiaris H, Mythreye K, Pena MM, Broude EV, Roninson IB. CDK8 selectively promotes the growth of colon cancer metastases in the liver by regulating gene expression of TIMP3 and matrix metalloproteinases. Cancer Res 2018; 78(23): 6594–6606

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Westerling T, Kuuluvainen E, ıMaäkelaä TP. Cdk8 is essential for preimplantation mouse development. Mol Cell Biol 2007; 27(17): 6177–6182

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chung HL, Mao X, Wang H, Park YJ, Marcogliese PC, Rosenfeld JA, Burrage LC, Liu P, Murdock DR, Yamamoto S, Wangler MF, Undiagnosed Diseases Network, Chao HT, Long H, Feng L, Bacino CA, Bellen HJ, Xiao B. De novo variants in CDK19 are associated with a syndrome involving intellectual disability and epileptic encephalopathy. Am J Hum Genet 2020; 106(5): 717–725

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Fisher RP. Taking aim at glycolysis with CDK8 inhibitors. Trends Endocrinol Metab 2018; 29(5): 281–282

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Koehler MF, Bergeron P, Blackwood EM, Bowman K, Clark KR, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L, Salphati L, Schmidt S, Schneider EV, Wu J, Beresini MH. Development of a potent, specific CDK8 kinase inhibitor which phenocopies CDK8/19 knockout cells. ACS Med Chem Lett 2016; 7(3): 223–228

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yu DS, Cortez D. A role for CDK9-cyclin K in maintaining genome integrity. Cell Cycle 2011; 10(1): 28–32

    CAS  PubMed  PubMed Central  Google Scholar 

  106. De Falco G, Bellan C, D’Amuri A, Angeloni G, Leucci E, Giordano A, Leoncini L. Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther 2005; 4(3): 277–281

    CAS  PubMed  Google Scholar 

  107. Egloff S. CDK9 keeps RNA polymerase II on track. Cell Mol Life Sci 2021; 78(14): 5543–5567

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Boffo S, Damato A, Alfano L, Giordano A. CDK9 inhibitors in acute myeloid leukemia. J Exp Clin Cancer Res 2018; 37(1): 36

    PubMed  PubMed Central  Google Scholar 

  109. Lui GYL, Grandori C, Kemp CJ. CDK12: an emerging therapeutic target for cancer. J Clin Pathol 2018; 71(11): 957–962

    CAS  PubMed  Google Scholar 

  110. Juan HC, Lin Y, Chen HR, Fann MJ. Cdk12 is essential for embryonic development and the maintenance of genomic stability. Cell Death Differ 2016; 23(6): 1038–1048

    CAS  PubMed  Google Scholar 

  111. Bösken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, Anand K, Fisher RP, Eick D, Geyer M. The structure and substrate specificity of human Cdk12/Cyclin K. Nat Commun 2014; 5(1): 3505

    PubMed  Google Scholar 

  112. Paculová H, Kohoutek J. The emerging roles of CDK12 in tumorigenesis. Cell Div 2017; 12(1): 7

    PubMed  PubMed Central  Google Scholar 

  113. Quereda V, Bayle S, Vena F, Frydman SM, Monastyrskyi A, Roush WR, Duckett DR. Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer. Cancer Cell 2019; 36(5): 545–558.e7

    CAS  PubMed  Google Scholar 

  114. Marineau JJ, Hamman KB, Hu S, Alnemy S, Mihalich J, Kabro A, Whitmore KM, Winter DK, Roy S, Ciblat S, Ke N, Savinainen A, Wilsily A, Malojcic G, Zahler R, Schmidt D, Bradley MJ, Waters NJ, Chuaqui C. Discovery of SY-5609: a selective, noncovalent inhibitor of CDK7. J Med Chem 2022; 65(2): 1458–1480

    CAS  PubMed  Google Scholar 

  115. Greifenberg AK, Honig D, Pilarova K, Duster R, Bartholomeeusen K, Bosken CA, Anand K, Blazek D, Geyer M. Structural and functional analysis of the Cdk13/cyclin K complex. Cell Rep 2016; 14(2): 320–331

    CAS  PubMed  Google Scholar 

  116. Fan Z, Devlin JR, Hogg SJ, Doyle MA, Harrison PF, Todorovski I, Cluse LA, Knight DA, Sandow JJ, Gregory G, Fox A, Beilharz TH, Kwiatkowski N, Scott NE, Vidakovic AT, Kelly GP, Svejstrup JQ, Geyer M, Gray NS, Vervoort SJ, Johnstone RW. CDK13 cooperates with CDK12 to control global RNA polymerase II processivity. Sci Adv 2020; 6(18): eaaz5041

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ito M, Tanaka T, Toita A, Uchiyama N, Kokubo H, Morishita N, Klein MG, Zou H, Murakami M, Kondo M, Sameshima T, Araki S, Endo S, Kawamoto T, Morin GB, Aparicio SA, Nakanishi A, Maezaki H, Imaeda Y. Discovery of 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective cyclin-dependent kinase 12 (CDK12) inhibitors. J Med Chem 2018; 61(17): 7710–7728

    CAS  PubMed  Google Scholar 

  118. Riching KM, Mahan S, Corona CR, McDougall M, Vasta JD, Robers MB, Urh M, Daniels DL. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chem Biol 2018; 13(9): 2758–2770

    CAS  PubMed  Google Scholar 

  119. Riching KM, Schwinn MK, Vasta JD, Robers MB, Machleidt T, Urh M, Daniels DL. CDK family PROTAC profiling reveals distinct kinetic responses and cell cycle-dependent degradation of CDK2. SLAS Discov 2021; 26(4): 560–569

    CAS  PubMed  Google Scholar 

  120. Dar AC, Shokat KM. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem 2011; 80(1): 769–795

    CAS  PubMed  Google Scholar 

  121. Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci 2015; 36(7): 422–439

    CAS  PubMed  Google Scholar 

  122. Wu P, Nielsen TE, Clausen MH. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today 2016; 21(1): 2–10

    Google Scholar 

  123. Fang Z, Grutter C, Rauh D. Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol 2013; 8(1): 28–70

    Google Scholar 

  124. Roskoski RJr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 2016; 103: 26–38

    CAS  PubMed  Google Scholar 

  125. Simard JR, Rauh D. FLiK: a direct-binding assay for the identification and kinetic characterization of stabilizers of inactive kinase conformations. Methods Enzymol 2013; 238: 137–171

    Google Scholar 

  126. Pellerano M, Tcherniuk S, Perals C, Ngoc Van TN, Garcin E, Mahuteau-Betzer F, Teulade-Fichou MP, Morris MC. Targeting conformational activation of CDK2 kinase. Biotechnol J 2017; 12(8): 1600231

    Google Scholar 

  127. Prével C, Pellerano M, Van TN, Morris MC. Fluorescent biosensors for high throughput screening of protein kinase inhibitors. Biotechnol J 2013; 9(2): 223–262

    Google Scholar 

  128. Prével C, Kurzawa L, Van TN, Morris MC. Fluorescent biosensors for drug discovery new tools for old targets—screening for inhibitors of cyclin-dependent kinases. Eur J Med Chem 2013; 88: 73–88

    Google Scholar 

  129. Zheng M, Liu Y, Wu C, Yang K, Wang Q, Zhou Y, Chen L, Li H. Novel PROTACs for degradation of SHP2 protein. Bioorg Chem 2021; 110: 103788

    Google Scholar 

  130. Ben Geoffrey AS, Kulkarni NM, Agrawal D, Vetrivel R, Gurram K. A new in-silico approach for PROTAC design and quantitative rationalization of PROTAC mediated ternary complex formation. bioRxiv 2022: 2022.2007.2011.399663

  131. Zheng S, Tan Y, Wang Z, Li C, Zhang Z, Sang X, Chen H, Yang Y. Accelerated rational PROTAC design via deep learning and molecular simulations. Nat Mach Intell 2022; 3(9): 739–738

    Google Scholar 

  132. Li F, Hu Q, Zhang X, Sun R, Liu Z, Wu S, Tian S, Ma X, Dai Z, Yang X, Gao S, Bai F. DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs. Nat Commun 2022; 13(1): 7133

    PubMed  PubMed Central  Google Scholar 

  133. Hsu JH, Rasmusson T, Robinson J, Pachl F, Read J, Kawatkar S, O’Donovan DH, Bagal S, Code E, Rawlins P, Argyrou A, Tomlinson R, Gao N, Zhu X, Chiarparin E, Jacques K, Shen M, Woods H, Bednarski E, Wilson DM, Drew L, Castaldi MP, Fawell S, Bloecher A. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem Biol 2020; 27(1): 31–36.e17

    Google Scholar 

  134. Schreiber SL. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000; 287(2360): 1963–1969

    Google Scholar 

  135. Gerry CJ, Schreiber SL. Recent achievements and current trajectories of diversity-oriented synthesis. Curr Opin Chem Biol 2020; 26: 1–9

    Google Scholar 

  136. Guney T, Wenderski TA, Boudreau MW, Tan DS. Synthesis of benzannulated medium-ring lactams via a tandem oxidative dearomatization-ring expansion reaction. Chemistry (Easton) 2018; 23(20): 13120–13127

    Google Scholar 

  137. Westphal MV, Hudson L, Mason JW, Pradeilles JA, Zecri FJ, Briner K, Schreiber SL. Water-compatible cycloadditions of oligonucleotide-conjugated strained allenes for DNA-encoded library synthesis. J Am Chem Soc 2020; 132(17): 7776–7782

    Google Scholar 

  138. Cheng J, Li X. Development and application of activity-based fluorescent probes for high-throughput screening. Curr Med Chem 2022; 29(10): 1739–1726

    CAS  PubMed  Google Scholar 

  139. Oke A, Sahin D, Chen X, Shang Y. High throughput screening for drug discovery and virus detection. Comb Chem High Throughput Screen 2022; 22(9): 1518–1533

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Key R&D Program of China (Nos. 2021YFA1302100, 2020YFE0202200, and 2021YFA1300200), National Natural Science Foundation of China (No. 22120334), Fellowship of China Postdoctoral Science Foundation (No. 2021M701923), and the Foundation of Shuimu Tsinghua Scholar Program (No. 2021SM110).

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  1. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China

    Liguo Wang, Zhouli Yang, Guangchen Li, Yongbo Liu & Yu Rao

  2. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China

    Chao Ai

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  1. Liguo Wang
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Correspondence to Chao Ai or Yu Rao.

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Conflicts of interest Liguo Wang, Zhouli Yang, Guangchen Li, Yongbo Liu, Chao Ai, and Yu Rao declare no conflict interests.

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Wang, L., Yang, Z., Li, G. et al. Discovery of small molecule degraders for modulating cell cycle. Front. Med. 17, 823–854 (2023). https://doi.org/10.1007/s11684-023-1027-5

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