Fragment-based Drug Design, Synthesis And Activity Studies Of Mcl-1Inhibitors

Bcl-2-like inhibitor is the hot spot and frontier of targeted antitumor drugs. It has been well established that Bcl-2-like inhibitor held promising therapy including targeted, low-toxic, high potency compared with cytotoxic agents. Therefore it is significant for the design and synthesis of some new small molecule Bcl-2-like inhibitor to study the structure-activity relashionship and the principle of fragment-based approach.Compound3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) had been verified previously by functional studies that it is a Mcl-l/Bcl-2dual inhibitor and a pure BH3mimetic. Up to now, it is the only molecule that functions through occupying the BH3groove of Mcl-1and Bcl-2proteins. Previous studies have shown the the binding modes of S1complexes with Mcl-1and Bcl-2proteins. A hydrogen bonding network could be formed between carbonyl group of S1and R263of Mcl-1and R146of Bcl-2, respectively. The thiomorpholine of SI occupied the p2pockets of Mcl-1/Bcl-2and the cyano extended into the p4pockets of Mcl-1/Bcl-2. however, the poor aqueous solubility of S1due to the rigid plane structure would significantly reduce its drugability.Thus, we applied fragment-based approach to defragment S1into three fragments. Ligand efficiency value and in combination with computer docking studies was used in the fragment hit selection phase. We identified Compound3with a2-hydroxypyridine core as the starting-fragment. The molecular growth of compound3was guided by the analysis of ligand efficiency evaluation and fit quality score. At last we got4nanomoler inhibitors of Mcl-1:N-isopropyl-5-(4-isopropylthiophenol)-2-hydroxynicotin-amide (12a),N-butyl-5-(4-isopropylthiophenol)-2-hydroxynicotin-amide (12b), N-benzyl-5-(4-isopropylthiophenol)-2-hydroxynicotinamide (12c), and N-phenylpropyl-5-(4-isopropylthiophenol)-2-hydroxynicotinamide (12d). The most potent compound12c binding to Mcl-1with an IC50value of56nM, similar to the initial compound S1(IC5o=48nM). Excitingly, the water-solubility of12c is much better than S1. Excitingly, as disrupting the rigid plane structure,12c shows a7-fold improved solubility (0.051g/L) compared with S1(0.007g/L) which fulfilled the requirements of drug likeness.12c all shows good inhibitory activity to MCF-7and K562cell lines.