3 years ago

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen
Philip P. Chamberlain, John F. Boylan, Rama Krishna Narla, Dan Zhu, Leo Barnes, Stacie S. Canan, Gordafaried Deyanat-Yazdi, Laurie LeBrun, Andrew Calabrese, Dan Cashion, Mark Nagy, Ming Chen, Dale Robinson, Katerina Leftheris, Sogole Bahmanyar, Roy Harris, Tam Tran, Paul Erdman, Silvia Delker, Yang Tang, Mehran F. Moghaddam, Jason Katz, Jennifer R. Riggs, Xiaohui Peng, Barbra Pagarigan, Lida Tehrani, Jan Elsner, Terra Miller, Dehua Huang
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01223

DOI: 10.1021/acs.jmedchem.7b01223

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