Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy

J Med Chem. 2019 May 9;62(9):4401-4410. doi: 10.1021/acs.jmedchem.8b01869.

Jennifer R Riggs ¹, Jan Elsner ¹, Dan Cashion ¹, Dale Robinson ¹, Lida Tehrani ¹, Mark Nagy ¹, Kimberly E Fultz ¹, Rama Krishna Narla ¹, Xiaohui Peng ¹, Tam Tran ¹, Ashutosh Kulkarni ¹, Sogole Bahmanyar ¹, Kevin Condroski ¹, Barbra Pagarigan ¹, Gustavo Fenalti ¹, Laurie LeBrun ¹, Katerina Leftheris ¹, Dan Zhu ¹, John F Boylan ¹

Affiliations

Affiliation

1 Celgene Corporation , 10300 Campus Point Drive, Suite 100 , San Diego , California 92121 , United States.

PMID: 30998356 DOI: 10.1021/acs.jmedchem.8b01869

Abstract

Triple negative breast Cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.

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