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

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
• Previous work identified dual TTK/CLK2 inhibitors with efficacy in TNBC models.

Purpose of the Study:

• To optimize pharmacokinetic properties and kinome selectivity of TTK inhibitors.
• To identify potent, selective, and orally bioavailable TTK inhibitors for TNBC treatment.

Main Methods:

• Structure-activity relationship (SAR) studies of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine series.
• Evaluation of single-agent efficacy in a TNBC xenograft model.
• Optimization from intravenous (IV)-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor.

Main Results:

• Identification of a new series of potent, selective, orally bioavailable TTK inhibitors.
• Demonstrated significant single-agent efficacy in a TNBC xenograft model.
• Achieved efficacy without observable body weight loss in the xenograft model.

Conclusions:

• The optimized 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine series represents a promising therapeutic strategy for TNBC.
• The development successfully transitioned from an IV-dosed dual inhibitor to an orally bioavailable single TTK inhibitor.
• This advancement provides a potential new treatment option for patients with triple-negative breast cancer.