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
  • 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.