Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability.
Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability.
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发现具有高亲和力、选择性和口服生物利用度的 3,5-二甲基-4-磺酰基-1H-吡咯基骨髓细胞白血病 1 抑制剂。
DOI：
10.1021/acs.jmedchem.1c00682
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发表时间：
2021-08
影响因子：
7.3
通讯作者：
Jiang Zheng-Yu
中科院分区：
文献类型：
--
作者：
Zhu Peng-Ju;Yu Ze-Zhou;Lv Yi-Fei;Zhao Jing-Long;Tong Yuan-Yuan;You Qi-Dong;Jiang Zheng-Yu
髓样细胞白血病1（Myeloid cell leukemia 1，Mcl-1）蛋白是一种重要的细胞凋亡负调控因子，开发Mcl-1抑制剂已成为肿瘤治疗的重要策略。本文介绍了基于3，5-二甲基-4-磺酰基-1H-吡咯的Mcl-1抑制剂的合理设计、合成及构效关系研究。逐步优化具有主要Mcl-1抑制（52%@30 μM）的命中化合物11导致发现最有效的化合物40，其具有高亲和力（Kd = 0.23 nM）和优于其它Bcl-2家族蛋白的上级选择性（> 40，000倍）。机制研究表明，40可以激活细胞凋亡信号通路中的Mcl-1依赖的方式。其中40个具有良好的理化性质和药动学特征（F% = 41.3%）。此外，口服施用40具有良好的耐受性，以有效抑制MV 4 -11异种移植模型中的肿瘤生长（T/C = 37.3%）。总的来说，这些发现暗示化合物40是一种有前途的抗肿瘤剂，值得进一步的临床前评价。
Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
7.3
作者：
Papatzimas, James W.;Gorobets, Evgueni;Derksen, Darren J.
通讯作者：
Derksen, Darren J.
影响因子：
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作者：
Cohen NA;Stewart ML;Gavathiotis E;Tepper JL;Bruekner SR;Koss B;Opferman JT;Walensky LD
通讯作者：
Walensky LD
影响因子：
7.3
作者：
Xing Lu;Yan-cheng Liu;C. Orvig;H. Liang;Zhenfeng Chen
通讯作者：
Xing Lu;Yan-cheng Liu;C. Orvig;H. Liang;Zhenfeng Chen
影响因子：
7.3
作者：
Friberg, Anders;Vigil, Dominico;Zhao, Bin;Daniels, R. Nathan;Burke, Jason P.;Garcia-Barrantes, Pedro M.;Camper, DeMarco;Chauder, Brian A.;Lee, Taekyu;Olejniczak, Edward T.;Fesik, Stephen W.
通讯作者：
Fesik, Stephen W.