Review articleDual-target kinase drug design: Current strategies and future directions in cancer therapy
Graphical abstract
Introduction
Protein kinases have been emerging as a major class of drug targets for pharmacological intervention, as a number of such kinases are implicated in the progression of human cancers [1,2]. Hitherto, to our knowledge, about 50 kinase inhibitors have been approved by the US Food and Drug Administration (FDA), and among them, 45 kinase inhibitors are directed toward the current cancer treatment. Consequently, much effort has been devoted to the development of small-molecule drugs that directly interfere with the catalytic activities of some targetable protein kinases. Despite typically being developed against individual or more targets, small-molecule inhibitors of protein kinases often exhibit considerable cross-reactivities because they are able to target conserved structural elements, such as purine nucleotide-binding pockets of protein kinases [3]. Recently, treatment with single-target drug has been widely reported to result in the resistance to chemotherapy [4]. Usually, resistant mechanisms can be classified into two types: ‘on-target’ and ‘off-target’. On one hand, on-target resistance occurs by altering the primary target of a drug, which limits its ability to inhibit the activity of its target. Hurdles of conventional single-target drugs can limit the accessibility of these drugs to tumor tissues [5]. Subsequently, a higher drug dose should be required, leading to non-specific targeting and intolerable cytotoxicity [6]. Relatively high epidermal growth factor receptor (EGFR) mutations are observed in lung cancer patients. On the other hand, off-target resistance often occurs when signaling events downstream of or parallel to targeted protein kinases are activated, which favors tumor cell growth and survival. It suggests that off-target resistance in patients treated with TRK inhibitors activates the mitogen-activated protein kinase (MAPK) signaling [7]. To seek the solution of single-target drug chemotherapeutic cancer treatment, the combination therapy has been recently adopted for clinical uses [8]. Notably, the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) has been approved for the treatment of metastatic melanoma with BRAF mutations [9]. Firstly, tumors with BRAF mutations depend on the extracellular regulated kinase (ERK) signaling pathway for proliferation [10]. Secondly, MEK can also feedback-activate RAF, cut off this feedback, and thus enhance pathway suppression [11]. Lastly, long-term use of the RAF inhibitor vemurafenib can lead to oncogene-induced senescence in the RAS-BRAF-MEK signaling pathway, which enhances cellular responses. As mentioned above, patients with this resistance may benefit from synergistic treatment with BRAF-MEK inhibitors [12]. Moreover, EGFR, a member of the transmembrane receptor tyrosine kinase (RTK) family, is associated with diverse types of cancer. Resistance to tyrosine kinase inhibitors (TKIs) has been reported to frequently occur in EGFR-mutated cancer patients. Consequently, non–small cell lung cancer (NSCLC) patients with mutant EGFR who received erlotinib and gefitinib have been accompanied with dramatic tumor regression [13]. To address the aforementioned problems, polypharmacology is introduced to treat currently incorrigible diseases and guides developments of compounds with safer, more effective, and affordable medicines. Also, polypharmacology can involve the combinations and/or multitargeted drugs [14]. More recently, the combination treatment with aurora kinase and EGFR inhibitors has been demonstrated to directly eliminate residual cancer cells without the emergence of genetic resistance [15]. Under some circumstances, the combination therapy might have an additive and even synergistic effects in theory; however, it often leads to some unpredictable side-effects, such as an increased toxicity. As an alternative strategy for combination therapy, dual-target or multi-target drugs have a lower risk of drug interactions and better pharmacokinetics (PK) and safety profiles. In addition, a dual-target kinase drug could help avoiding the two drug interactions, poor patient compliance, adverse off-target effects and high development costs. There are a number of dual-target or multi-target drugs that have been approved by FDA for anti-cancer treatment. Alectinib (Alecensa, Hoffman-LaRoche) is dual-targeted (ALK and RET) drug for ALK+ NSCLC [16]. Dasatinib (Sprycel, Bristol-Myers Squibb) has nine known targets (BCR-Abl, EGFR, Src, Lck, Yes, Fyn, Kit, EphA2, PDGFR) for CML or ALL. As mentioned above, dual/multi-targeted kinase inhibitors are well adapted to develop potent anti-cancer drugs [17]. In this review, we provide the current drug design strategies aiming at dual-target kinase, including medicinal chemistry design (e.g., drug repurposing, skeleton modification, and linked/merged/fused pharmacophore), computational design (e.g., docking-, pharmacophore-, fragment-based, and even artificial intelligence (AI)-based design approaches), which would shed new light on the future directions of dual-target kinase drug design for future cancer therapeutics.
Section snippets
Repurposing of dual-target kinase drugs
The approved or investigational drug may involve in more than one pathology and modulate the activity of unpredicted targets. Drug repositioning is introduced to explore a new therapeutic area. The cost and time of research would be substantially decreased, because of the prior knowledge of the metabolism and possible side effects. It also has certain limitations. Many successful examples are from large-scale research on drug properties and unexpectedly discovery. It is difficult to translated
Computational design of dual-target kinase drugs in cancer
Computational design is another effective method to design novel dual-target drugs, especially for new kinase targets with not reported drugs. Recently, some kinase inhibitors have attracted increasing attention due to the structural diversity of these single-target inhibitors and the limitation of their target combinations. Some inhibitors are designed based upon kinase structures, and multi-target compounds are designed by the involvement of pharmacochemistry, proteomics, and computational
Challenges and future perspectives
Dual-target drugs have therapeutic advantages over the combination therapies because they weaken problems including different bioavailabilities, metabolisms, and antagonistic effects. Compared to single-target drugs, dual-target drugs may demonstrate either their additive or synergistic effects.
Despite their evident growth, dual-targeted inhibitors are attributed with several challenges. A critical challenge is how to control the adverse effects of dual-targeted activities. The dual inhibitors
Conclusions
Hitherto, more than 500 protein kinases have been reported encoded by the human genome, and most of them are able to regarded as potential drugable targets in cancer therapeutics. Accordingly, nearly 400 types of known kinase inhibitors have also been designed, which may be a relatively important branch of medicinal chemistry. Since the first targeted small-molecule kinase inhibitor, imatinib, is applied into the clinic, more than forty types of small-molecule kinase inhibitors have been
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.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81922064, Grant No. 81673455, Grant No. 81874290 and Grant No. 81673290).
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These authors contributed equally to this work.