1区 · 医学
Article
作者: Elsner, Jan ; Katz, Jason ; Leftheris, Katerina ; Barnes, Leo ; Erdman, Paul ; Canan, Stacie S. ; Boylan, John F. ; Moghaddam, Mehran F. ; Pagarigan, Barbra ; Chamberlain, Philip P. ; LeBrun, Laurie ; Narla, Rama Krishna ; Nagy, Mark ; Zhu, Dan ; Chen, Ming ; Harris, Roy ; Bahmanyar, Sogole ; Robinson, Dale ; Huang, Dehua ; Tran, Tam ; Cashion, Dan ; Tang, Yang ; Miller, Terra ; Peng, Xiaohui ; Calabrese, Andrew ; Delker, Silvia ; Tehrani, Lida ; Deyanat-Yazdi, Gordafaried ; Riggs, Jennifer R.
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.