Fragment-based Drug Design,Synthesis And Anticancer Activty Study Of Bcl-2 Inhibitors

Targeting the interface between proteins has huge therapeutic potential, but discovering small molecule drugs that disrupt protein-protein interactions is an enormous challenge. Bcl-2 inhibitors have a big impact on cancer therapy. As such, the potential for novel compounds that hit Mcl-1/Bcl-2 may rest for the time in our lab.Firstly, we recently described the discovery of a dual inhibitor of Mcl-1/Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1).Here we report a structure-guided design in combination with SAR studies to exploit the difference in the p2 binding pocket of Mcl-1 and Bcl-2, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (B8) was obtained, which showed significant enhanced IC50 against Mcl-1 (5nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over S1.Secondly, we focus on Mcl-1 protein inhibitors. Mcl-1 is one of the anti-apoptotic Bcl-2 members. We used to perform structure-based structure activity relationship studies to modify S1 which aimed to get more potent inhibitors. In terms of affinity, we were successful. Unfortunately, the solubility of the obtained molecules is as poor as their parent S1. We believed that we need an alternative way to get more drug-like Mcl-1 inhibitors based on S1.Here, we applied fragment-based approach to get more drug-like Mcl-1 inhibitors based on S1. We firstly defragmented S1 into fragments to find an ideal hit. We got two fragments whose masses and affinities are acceptable to be selected as hit. But they exhibited very different LE.We were interested to benchmark the expectations of upcoming fragment hits with regard to LE, enable better evaluation in the fragment hit selection phase and subsequent efficiently optimize fragments, as well as to yield drug candidates. Thus, we optimized from these two different starting points and compared their LE trends. Except for an expecting soluble Mcl-1 inhibitor and pure BH3 mimetic 4g that showed orally antitumor ability in a mouse xenograft model, we constructed a prediction map for Mcl-1 inhibitors and revealed that core modifications should be high lighted in optimization of Mcl-1 inhibitors.