Recent advances in development of hetero-bivalent kinase inhibitors

https://doi.org/10.1016/j.ejmech.2021.113318Get rights and content

Highlights

  • Bivalent protein kinase inhibitors reported until 2020 have been described.

  • Bivalent inhibitors overcoming limitations of kinase inhibitors are described.

  • Limitations and perspectives for bivalent protein kinase inhibitors are discussed.

  • This review cites 195 references.

Abstract

Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is the development of bivalent kinase inhibitors, which consist of two connected fragments, each bind to a dissimilar binding site of the bisubstrate enzyme. The main advantage of bivalent (type V) kinase inhibitors is generating more interactions with target enzymes that can enhance the molecules’ selectivity and affinity compared to single-site inhibitors. Earlier type V inhibitors were not suitable for the cellular environment and were mostly used in in vitro studies. However, recently developed bivalent compounds have high kinase affinity, high biological and chemical stability in vivo. This review summarized the hetero-bivalent kinase inhibitors described in the literature from 2014 to the present. We attempted to classify the molecules by serine/threonine and tyrosine kinase inhibitors, and then each target kinase and its hetero-bivalent inhibitor was assessed in depth. In addition, we discussed the analysis of advantages, limitations, and perspectives of bivalent kinase inhibitors compared with the monovalent kinase inhibitors.

Introduction

Bivalent ligands are defined as molecules that consist of two discrete recognition fragments connected through a spacer [1]. Although the bivalent system is predominantly encountered in naturally occurring antibodies, it has been widely applied to unnatural therapeutic agents by combining two different antibodies or small molecular fragments to generate hetero-bivalent compounds [2]. Since such ligands have the potential to interact with two pharmacophores, they can synergize to enhance the affinity for their targets. The overall strength of multiple affinities from entire binding interactions is defined as avidity [3] and avidity-based bivalent approaches successfully employed to develop powerful protein kinase inhibitors [4,5].

Kinase inhibitors are classified into six types (type I–VI) based on the structural interaction between the target kinase and the inhibitor [6]. Type I and type II protein kinase inhibitors bind to adenine binding pocket and form hydrogen bonds with the hinge regions that connect the enzyme’s lobes. For detail, Type I inhibitors directly bind to an active protein kinase conformation (DFG-Asp in, αC-helix in). On the other hand, Type II inhibitors preferentially lock the inactive conformation of the target protein kinase. Both Type III and Type IV inhibitors are allosteric inhibitors and distinguished by the location of the binding site on the target [7]. Type III inhibitors bind next to ATP-bound pockets, and type IV inhibitors act on the allosteric pocket away from the ATP-binding site [8]. Type V inhibitors are bivalent compounds that can interact with two different parts of the protein kinase region. Type VI inhibitors are the covalent type. Therefore, they irreversibly inhibit the target enzyme.

Hetero-bivalent (Type V) inhibitors consist of three components as depicted in Fig. 1. In general, they possess an ATP-competitive ligand and pseudosubstrate peptide that are covalently connected through a linker. This unique structural feature permits to bind of both ATP and peptide binding sites simultaneously, and therefore, leading compounds to have high selectivity and avidity for the target tyrosine and serine/threonine kinase. Despite these advantages, limited reviews of type V inhibitor have been reported so far, and the most recent reviews of type V bivalent protein kinase inhibitors have been presented by Gower et al. in 2014 [9]. While, a review of type III inhibitor, an allosteric kinase inhibitor, was published in 2020, and the covalent ‘type VI’ inhibitor was reviewed by Z. Zhao et al. in 2018 [10,11].

In this review, we compile structures of various bivalent kinase inhibitors reported to date from 2014. Our focus has been placed on categorizing the bivalent kinase inhibitors based on their target. We collect 17 serine/threonine bivalent kinase inhibitors and 4 tyrosine bivalent kinase inhibitors, and the specific structure and reference are shown in Table 1 and Table 2. In the last stage, we discuss advantages and limitations of emerging bivalent kinase inhibitors by comparing it with monovalent kinase inhibitors. Based on these current advances, we further provide our perspectives on the field of bivalent kinase inhibitor research.

Section snippets

Bivalent inhibitors of serine/threonine protein kinases

Among the more than 500 human kinases, 385 members of kinases are serine/threonine (Ser/Thr) protein kinases, which phosphorylate the hydroxyl group of serine or threonine of specific substrates. Ser/Thr kinases play essential roles in the regulation of various cellular processes, especially signaling pathways via phosphorylation cascades [[29], [30], [31]]. Although Ser/Thr protein kinases comprise more than half of all human protein kinases, only 11 of the 52 drugs approved until January 2020

Discussion

This section discusses the challenges and opportunities for bivalent kinase inhibitors by exploring the current status of representative monovalent kinase inhibitors. The brief analysis of representative monovalent kinase inhibitors for each target is covered in section 3.1. A detailed discussion on the limitations and perspectives for bivalent kinase inhibitors is presented in section 3.2.

Conclusions

Over the past 20 years, researchers have made many efforts to target two different binding sites on a particular kinase. Their unremitting works have yielded several type V hetero-bivalent kinase inhibitors. To highlight recent advances in type V inhibitors, target proteins were classified by serine/threonine and tyrosine kinases and discussed in detail for each kinase by reviewing all relevant articles from 2014 to the present. Various hetero-bivalent ligands were designed and built through a

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07045101) and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (NRF-2017M3A9G7072568).

References (195)

  • R. Roskoski

    Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update

    Pharmacol. Res.

    (2020)
  • D.A. Walsh et al.

    An adenosine 3’,5’-monophosphate-dependant protein kinase from rabbit skeletal muscle

    J. Biol. Chem.

    (1968)
  • D.A. Walsh et al.

    Substrate diversity of the cAMP-dependent protein kinase: regulation based upon multiple binding interactions

    Curr. Opin. Cell Biol.

    (1992)
  • S.S. Taylor et al.

    Chapter 179 - cAMP-dependent protein kinase

  • S.S. Taylor et al.

    PKA: a portrait of protein kinase dynamics

    Biochim. Biophys. Acta

    (2004)
  • S.S. Taylor et al.

    Dynamics of signaling by PKA

    Biochim. Biophys. Acta

    (2005)
  • A.C. Hines et al.

    Design, synthesis, and characterization of an ATP-peptide conjugate inhibitor of protein kinase A

    Bioorg. Med. Chem. Lett

    (2004)
  • M. Loog et al.

    Adenosine-5’-carboxylic acid peptidyl derivatives as inhibitors of protein kinases, Bioorg

    Med. Chem. Lett.

    (1999)
  • C.D. Shomin et al.

    Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): optimization and selectivity profiling

    Bioorg. Med. Chem.

    (2009)
  • A. Pflug et al.

    Diversity of bisubstrate binding modes of adenosine analogue-oligoarginine conjugates in protein kinase a and implications for protein substrate interactions

    J. Mol. Biol.

    (2010)
  • A. Vaasa et al.

    High-affinity bisubstrate probe for fluorescence anisotropy binding/displacement assays with protein kinases PKA and ROCK

    Anal. Biochem.

    (2009)
  • M. Kasari et al.

    Time-gated luminescence assay using nonmetal probes for determination of protein kinase activity-based disease markers

    Anal. Biochem.

    (2012)
  • G. Burnett et al.

    The enzymatic phosphorylation of proteins

    J. Biol. Chem.

    (1954)
  • C. Cochet et al.

    Oligomeric structure and catalytic activity of G type casein kinase. Isolation of the two subunits and renaturation experiments

    J. Biol. Chem.

    (1983)
  • X. Shi et al.

    A novel casein kinase 2 alpha-subunit regulates membrane protein traffic in the human hepatoma cell line HuH-7

    J. Biol. Chem.

    (2001)
  • J.C. Reed et al.

    Cloning and disruption of CKB2, the gene encoding the 32-kDa regulatory beta’-subunit of Saccharomyces cerevisiae casein kinase II

    J. Biol. Chem.

    (1994)
  • A.I. Kalmykova et al.

    The Su(Ste) repeat in the Y chromosome and betaCK2tes gene encode predicted isoforms of regulatory beta-subunit of protein kinase CK2 in Drosophila melanogaster

    FEBS Lett.

    (1997)
  • C.C. Schneider et al.

    Modified tetrahalogenated benzimidazoles with CK2 inhibitory activity are active against human prostate cancer cells LNCaP in vitro

    Bioorg. Med. Chem.

    (2012)
  • P.J. Kennelly et al.

    Consensus sequences as substrate-specificity determinants for protein-kinases and protein phosphatases

    J. Biol. Chem.

    (1991)
  • L.A. Pinna et al.

    How do protein kinases recognize their substrates?

    Biochim. Biophys. Acta Mol. Cell Res.

    (1996)
  • J. Vahter et al.

    Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2

    Bioorg. Med. Chem.

    (2017)
  • R. Roskoski

    ERK1/2 MAP kinases: structure, function, and regulation

    Pharmacol. Res.

    (2012)
  • M.J. Garnett et al.

    Guilty as charged: B-RAF is a human oncogene

    Canc. Cell

    (2004)
  • W.E. Tidyman et al.

    The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

    Curr. Opin. Genet. Dev.

    (2009)
  • J.F. Tanti et al.

    Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation

    Curr. Opin. Pharmacol.

    (2009)
  • C. Montagut et al.

    Targeting the RAF-MEK-ERK pathway in cancer therapy

    Canc. Lett.

    (2009)
  • G. Vauquelin et al.

    Exploring avidity: understanding the potential gains in functional affinity and target residence time of bivalent and heterobivalent ligands

    Br. J. Pharmacol.

    (2013)
  • S.I. Rudnick et al.

    Affinity and avidity in antibody-based tumor targeting

    Cancer Biother. Radiopharm.

    (2009)
  • A.A. Profit et al.

    Bivalent inhibitors of protein tyrosine kinases

    J. Am. Chem. Soc.

    (1999)
  • V.S. Rodrik-Outmezguine et al.

    Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor

    Nature

    (2016)
  • J. Zhang et al.

    Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors

    Nature

    (2010)
  • C.M. Gower et al.

    Bivalent inhibitors of protein kinases

    Crit. Rev. Biochem. Mol. Biol.

    (2014)
  • X. Lu et al.

    New promise and opportunities for allosteric kinase inhibitors

    Angew. Chem. Int. Ed.

    (2020)
  • E. Restituyo et al.

    A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases

    Methods Mol. Biol.

    (2015)
  • M. Kriisa et al.

    Inhibition of CREB phosphorylation by conjugates of adenosine analogues and arginine-rich peptides, inhibitors of PKA catalytic subunit

    Chembiochem

    (2015)
  • O.E. Nonga et al.

    Inhibitors and fluorescent probes for protein kinase PKAcbeta and its S54L mutant, identified in a patient with cortisol producing adenoma

    Biosci. Biotechnol. Biochem.

    (2020)
  • J. Muller et al.

    Conceptional design of self-assembling bisubstrate-like inhibitors of protein kinase A resulting in a boronic acid glutamate linkage

    ACS Omega

    (2019)
  • G. Cozza et al.

    Design, validation and efficacy of bisubstrate inhibitors specifically affecting ecto-CK2 kinase activity

    Biochem. J.

    (2015)
  • M. Winiewska-Szajewska et al.

    Rational drug-design approach supported with thermodynamic studies - a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2

    Sci. Rep.

    (2019)
  • B.C. Lechtenberg et al.

    Structure-guided strategy for the development of potent bivalent ERK inhibitors

    ACS Med. Chem. Lett.

    (2017)
  • Cited by (16)

    • Kinase-targeting small-molecule inhibitors and emerging bifunctional molecules

      2022, Trends in Pharmacological Sciences
      Citation Excerpt :

      Up until 2010 approximately one SMKI per year was approved; in 2011–2015 approximately four SMKIs per year were approved; and approximately eight SMKI approvals per year has been the norm since 2017 (Figure 2) [3,4,7,8]. In addition to the classical types of type I and II inhibitors that bind at the ATP-binding pocket, growing numbers of inhibitors have been reported as allosteric type III and IV inhibitors [13], covalent inhibitors [14], and bivalent inhibitors [15,16], together with new chemical modalities, including molecular glues, proteolysis targeting chimera (PROTAC) [17] (Figure 1B–E), and other types of kinase-targeting, proximity-inducing bifunctional small molecules. In the following sections, we analyze and discuss the binding modes and mechanisms of inhibition for representative approved SMKIs in each class and highlight recent advances in the development of proximity-inducing bifunctional molecules as kinase degraders or modifiers to add or remove ubiquitination or phosphorylation.

    View all citing articles on Scopus

    These authors contributed equally to this work.

    View full text