Recent advances in development of hetero-bivalent kinase inhibitors
Graphical abstract
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).
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2022, Trends in Pharmacological SciencesCitation 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.
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These authors contributed equally to this work.