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 PMID: 28991472

Target-related Cytokines

2026-09-23

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

J Med Chem. 2017 Nov 9;60(21):8989-9002. doi: 10.1021/acs.jmedchem.7b01223.

Jennifer R Riggs ¹ , Mark Nagy ¹ , Jan Elsner ¹ , Paul Erdman ¹ , Dan Cashion ¹ , Dale Robinson ¹ , Roy Harris ¹ , Dehua Huang ¹ , Lida Tehrani ¹ , Gordafaried Deyanat-Yazdi ¹ , Rama Krishna Narla ¹ , Xiaohui Peng ¹ , Tam Tran ¹ , Leo Barnes ¹ , Terra Miller ¹ , Jason Katz ¹ , Yang Tang ¹ , Ming Chen ¹ , Mehran F Moghaddam ¹ , Sogole Bahmanyar ¹ , Barbra Pagarigan ¹ , Silvia Delker ¹ , Laurie LeBrun ¹ , Philip P Chamberlain ¹ , Andrew Calabrese ¹ , Stacie S Canan ¹ , Katerina Leftheris ¹ , Dan Zhu ¹ , John F Boylan ¹

Affiliations

Abstract

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.