Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.
Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.
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DOI：
10.1021/acs.jmedchem.9b01310
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发表时间：
2019-11
影响因子：
7.3
通讯作者：
G. Rescourio;Ana Z. Gonzalez;Salman Y. Jabri;Brian Belmontes;Gordon Moody;D. Whittington;Xin Huang;S. Caenepeel;M. Cardozo;A. Cheng;D. Chow;Hannah Dou;Adrie D Jones;R. Kelly;Yihong Li;M. Lizarzaburu;M. Lo;R. Mallari;C. Meleza;Y. Rew;S. Simonovich;Daqing Sun;S. Turcotte;Xuelei Yan;Simon G. Wong;Evelyn Yanez;Manuel Zancanella;Jonathan B. Houze;J. Medina;P. Hughes;Sean P. Brown
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文献类型：
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作者：
G. Rescourio;Ana Z. Gonzalez;Salman Y. Jabri;Brian Belmontes;Gordon Moody;D. Whittington;Xin Huang;S. Caenepeel;M. Cardozo;A. Cheng;D. Chow;Hannah Dou;Adrie D Jones;R. Kelly;Yihong Li;M. Lizarzaburu;M. Lo;R. Mallari;C. Meleza;Y. Rew;S. Simonovich;Daqing Sun;S. Turcotte;Xuelei Yan;Simon G. Wong;Evelyn Yanez;Manuel Zancanella;Jonathan B. Houze;J. Medina;P. Hughes;Sean P. Brown
抗凋亡蛋白Mcl-1的过度表达为一些癌细胞提供了生存优势，使得抑制该蛋白成为治疗某些类型肿瘤的有吸引力的治疗靶点。在此，我们报告了我们对鉴定一系列具有α-羟基苯基乙酸药效团或生物等异体的新型大环Mcl-1抑制剂的努力。这项工作导致发现1，一种有效的Mcl-1抑制剂（在OPM-2细胞活力测定中IC50 = 19 nM），在OPM-2多发性骨髓瘤异种移植模型中具有良好的药代动力学特性和出色的体内疗效。
Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.