Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity PMID: 34459599

ADC Targets in Oncology

2026-04-10

Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity

J Med Chem. 2021 Sep 9;64(17):12670-12679. doi: 10.1021/acs.jmedchem.1c00635.

Jan Elsner ¹ , Dan Cashion ¹ , Dale Robinson ¹ , Sogole Bahmanyar ¹ , Lida Tehrani ¹ , Kimberly E Fultz ¹ , Rama Krishna Narla ¹ , Xiaohui Peng ¹ , Tam Tran ¹ , Julius Apuy ¹ , Laurie LeBrun ¹ , Katerina Leftheris ¹ , John F Boylan ¹ , Dan Zhu ¹ , Jennifer R Riggs ¹

Affiliations

Abstract

TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast Cancer (TNBC) cell lines (8: TTK IC₅₀ = 3.0 nM; CAL-51 IC₅₀ = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC₅₀ = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC₅₀ = 3.0 nM; CAL-51 IC₅₀ = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.