Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

Abstract

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.

KinomeRun: An interactive utility for kinome target screening and interaction fingerprint analysis towards holistic visualization on kinome tree

“…Further, reanalysis was performed by specifying the explicit presence of halogen: 79 th position interactions in the All_pose_structure file and the resultant targets were mapped on to the kinome tree Figure 5a. The known wild targets of sorafenib: ABL1 (Kurosu, Ohki, Wu, Kagechika, & Miura, 2009), p38a (Namboodiri et al., 2010), CDK8 (Schneider et al., 2011), MET (Beizaei et al., 2019), TRKB (Kumar et al., 2009), FLT3, FLT1 (Wilhelm et al., 2004), RIPK1 (Martens et al., 2017), DDR1 (El‐Damasy, Cho, Nam, Pae, & Keum, 2016; Kitagawa et al., 2013) and the mutant targets such as JNK2 (functional disability due to this mutation is not reported, hence was considered as wild type; Broecker‐Preuss et al., 2015), BRAF V600E (Wan et al., 2004), KDR T940V (Okamoto et al., 2015), KIT mutant and KIT WT (Wilhelm et al., 2004) were also identified as top‐ranking hits as per the maximal number of interaction patterns, and EphB4 Y774E_A803V_V870I (functional disability due to this mutation is not reported, hence was considered as wild type; Wang et al., 2017), PEK D937N (but wild PEK inhibition is reported [Shiota et al., 2010]), FMS C667T_C830S_C907T (functional disability due to this mutation is not reported, hence was considered as wild type; Uitdehaag et al., 2011; Ullrich et al., 2011) were identified to be mapped on the kinome tree Figure 5a & Table S5. The other targets of sorafenib: CDK2 (WT) and MELK mutant were also found during target prioritization.…”

“…(b) Cartoon representation of 42 overlayed ABL1 structures with DFG out -αC out conformations to which imatinib/ponatinib binds. (c) Cartoon representation of six overlayed ABL1 structures with DFG out -αC out conformations which failed to bind with imatinib/ponatinib due difference in Chi-1 torsion angles [Colour figure can be viewed at wileyonlinelibrary.com] considered as wild type; Wang et al, 2017), PEK D937N (but wild PEK inhibition is reported [Shiota et al, 2010]), FMS C667T_C830S_C907T (functional disability due to this mutation is not reported, hence was considered as wild type; Uitdehaag et al, 2011;Ullrich et al, 2011) were identified to be mapped on the kinome tree Figure 5a & Table S5. The other targets of sorafenib: CDK2 (WT) and MELK mutant were also found during target prioritization.…”

Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper

“…Looking ahead, preclinical studies on single inhibitors targeting multiple molecules are being undertaken for both biologicals and SMDs with the dual IL‐4/IL‐13 blocking mAbs against their receptor subunit IL‐4Rα (dupilumab, Table ), with bi‐specific antibodies (eg, dual antagonists for IL‐4/IL‐13, CXCR3/CCR6, and CCR3/CD300a), and with multi‐target receptor tyrosine kinase inhibitors, so far developed for anti‐angiogenic treatment in lung cancer …”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Many proangiogenic factors have been identified including VEGF, Ang, ephrinB2, and Notch among others. Their receptors, VEGFR‐2, Tie‐2, and EphB4, all belong to the RTK family, which is a subfamily of protein kinases critical to cell growth, survival, and angiogenesis . VEGF is the most potent proangiogenic factor, and its binding to VEGFR‐2 promotes ECs survival, proliferation, and migration.…”

“…Their receptors, VEGFR-2, Tie-2, and EphB4, all belong to the RTK family, which is a subfamily of protein kinases critical to cell growth, survival, and angiogenesis. 41 VEGF is the most potent proangiogenic factor, and its binding to VEGFR-2 promotes ECs survival, proliferation, and migration. Ang and its receptor (Tie-2) are essential for vessel maturation, stabilization, and remodeling of vasculature.…”