Fragment-based discovery of novel phenyltriazolyl derivatives as allosteric type-I1/2 ALK inhibitors with promising antitumor effects.

Based on the high-throughput screening hit BY-1, a series of phenyltriazolyl derivatives were developed. Satisfyingly, most compounds were detected moderate to excellent antitumor effects against Karpas299 and H2228 cells. Among them, 12k bearing 4­hydroxypiperidinyl group exhibited the optimal activities against tested cells with IC50 values of 51 nM and 175 nM, as well as promising inhibitory effects on ALKWT (3.7 nM) and ALKL1196M (6.8 nM). Unlike the conventional type-I ALK inhibitors, molecular models identified 12k as an allosteric type-I1/2 inhibitor by forming key interactions in both the ATP binding region and the hydrophobic back pocket of ALK. Intriguingly, 12k could dose-dependently induce apoptosis on H2228 cell and inhibit colony formation and tumor cell migration. Taken together, the rationalization of 12k may shed new light on the identification of novel allosteric type-I1/2 ALK inhibitors.

Design, synthesis and anti-fibrosis evaluation of imidazo[1,2-a]pyridine derivatives as potent ATX inhibitors.

A series of imidazo[1,2-a]pyridine compounds bearing urea moiety (8-27) were designed, synthesized and evaluated for their ATX inhibitory activities in vitro by FS-3 based enzymatic assay. Delightfully, benzylamine derivatives (14-27) exhibited higher ATX inhibitory potency with IC50 value ranging from 1.72 to 497 nM superior to benzamide analogues (8-13). Remarkably, benzylamine derivative 20 bearing 4-hydroxypiperidine exerted an amazing inhibitory activity (IC50 = 1.72 nM) which exceeded the positive control GLPG1690 (IC50 = 2.90 nM). Simultaneously, the binding model of 20 with ATX was established which rationalized the well performance of 20 in enzymatic assay. Accordingly, further in vivo studies were carried out to evaluate direct anti-fibrotic effects of 20 through Masson staining. Notably, 20 effectively alleviated lung structural damage with fewer fibrotic lesions at an oral dose of 60 mg/kg, qualifying 20 as a promising ATX inhibitor for IPF treatment.

Harmine-inspired design and synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives bearing 1,3,4-oxadiazole moiety as potential tumor suppressors.

Standard chemotherapy and personalized target therapies are commonly used in patients with advanced non-small cell lung cancer (NSCLC). However, multidrug resistance (MDR) and tumor metastasis lead to the decline of therapeutic efficacy, which are closely related to epithelial-mesenchymal transition (EMT). Twist1, an EMT transcription factor, plays an essential role in promoting EMT, MDR and tumor metastasis. In view of the essential role of Twist1 in the tumorigenesis of NSCLC, developing antitumor small molecules that can suppress the expression of Twist1 is of far-reaching significance for the treatment of NSCLC. A series of novel benzo[d]imidazo[2,1-b]thiazole derivatives possessing 1,3,4-oxadiazole moiety were designed based on the structure of the first-in-class Twist1 inhibitor harmine. Among the synthetic twenty-two compounds, the compound containing 2-(piperidine-1-yl) ethyl exhibited remarkable anti-proliferative activity with IC50 value of 2.03 µM and 9.80 µM against A549 and H2228 cell lines superior to harmine (IC50 = 17.12 µM against A549, IC50 = 31.06 µM against H2228). Meanwhile, western blot assay showed that the optimal compound significantly down-regulated Twist1 protein expression in a dose-dependent manner and reduced Twist1 level better than harmine. Collectively, the promising compound was identified a potential antineoplastic lead with the ability of down-regulating Twist1 level.

Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors.

Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound 10c bearing a N-hydroxyethyl piperazinyl group was identified as the optimal ATX inhibitor with an IC50 value of 3.4 nM 10c exerted the most impressive antitumor effects, especially on Hep3B (0.58 µM) and RAW264.7 (0.63 µM) cell lines highly expressing ATX mRNA. Moreover, 10c could dose-dependently suppress the RAW264.7 cell migration rate in wound healing assay and significantly inhibit RAW264.7 cell colony formation. Meanwhile, 10c was capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together, 10c may serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases.