Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.</p

Discovery of Anilinopyrimidines as Dual Inhibitors of c‑Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure–activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds <b>3a</b>, <b>3b</b>, <b>3g</b>, <b>3h</b>, and <b>18a</b> exhibited potent antiproliferative effect against c-Met addictive cell lines with IC₅₀ values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with <b>3h</b> has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues

Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2‑<i>a</i>]pyridine Derivatives as Potent c‑Met Inhibitors

A series of imidazo­[1,2-<i>a</i>]­pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, <b>22e</b> was identified, with IC₅₀ values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound <b>22e</b> inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound <b>22e</b> significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (<i>F</i> = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of <b>22e</b> in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite <b>33</b> was generated by liver microsomes. To block the metabolic site, <b>42</b> was designed and synthesized for further evaluation. Taken together, the imidazo­[1,2-<i>a</i>]­pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation

Design, Synthesis, and Biological Evaluation of the First c‑Met/HDAC Inhibitors Based on Pyridazinone Derivatives

Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, <b>2m</b>, inhibited c-Met kinase and HDAC1, with IC₅₀ values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound <b>2m</b> inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule

Design and Optimization of a Series of 1‑Sulfonyl­pyrazolo[4,3‑<i>b</i>]pyridines as Selective c‑Met Inhibitors

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit <b>7</b>. By rational design, a novel sulfonyl­pyrazolo­[4,3-<i>b</i>]­pyridine <b>9</b> with improved DMPK properties was discovered. Further elaboration of π–π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound <b>46</b> was selected as a preclinical candidate for further anticancer drug development