Discovery and preclinical profile of YK-2168, a differentiated selective CDK9 inhibitor in clinical development

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Selective CDK9 inhibition shows promise for cancer treatment.
• Existing CDK9 inhibitors face challenges due to toxicity and lack of clear clinical winners.
• Novel agents with differentiated profiles are needed.

Purpose of the Study:

• To design and synthesize a novel series of selective CDK9 inhibitors.
• To identify a preclinical candidate with improved selectivity and pharmacokinetic properties.
• To evaluate the efficacy of the novel agent in solid tumor models.

Main Methods:

• Design and synthesis of novel azaindole compounds.
• Structure-activity relationship (SAR) studies to identify lead candidates.
• Preclinical evaluation of CDK9 selectivity, in vivo pharmacokinetics (PK), and efficacy in a gastric cancer cell line xenograft model.

Main Results:

• A novel azaindole series of selective CDK9 inhibitors was developed.
• YK-2168 demonstrated superior CDK9 selectivity compared to AZD4573 and BAY1251152.
• YK-2168 exhibited a differentiated intravenous PK profile and significant solid tumor efficacy in a preclinical gastric cancer model.

Conclusions:

• YK-2168 represents a promising preclinical candidate with improved CDK9 selectivity and efficacy.
• The novel azaindole scaffold offers a potential new therapeutic avenue for cancer treatment.
• YK-2168 is currently undergoing clinical development in China.