Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Current CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are approved for metastatic breast cancer.
• Abemaciclib demonstrates better tolerability due to preferential CDK4 inhibition over CDK6.
• There is a need for novel, biased CDK4 inhibitors with improved therapeutic profiles.

Purpose of the Study:

• To discover and characterize novel pyrimidine-indazole inhibitors with preferential CDK4 inhibition.
• To evaluate the preclinical efficacy and safety of TQB3616 compared to existing CDK4/6 inhibitors.
• To assess the pharmacokinetic profile and suitability of TQB3616 for clinical development.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted to identify lead compounds.
• Enzymatic and cellular proliferation assays were used to determine inhibitory potency.
• Pharmacokinetic (PK) studies were performed in multiple species.
• Good Laboratory Practice (GLP) safety studies were conducted.

Main Results:

• A series of pyrimidine-indazole inhibitors were discovered, leading to the identification of TQB3616.
• TQB3616 demonstrated superior enzymatic and cellular proliferation inhibitory potency compared to palbociclib and abemaciclib.
• TQB3616 exhibited a favorable PK profile and an excellent GLP safety profile.
• TQB3616 has advanced into Phase III clinical trials (NCT05375461, NCT05375461).

Conclusions:

• TQB3616 is a potent and selective CDK4 inhibitor with a differentiated profile.
• Its improved potency, favorable PK, and safety profile support its clinical development.
• TQB3616 represents a promising therapeutic candidate for metastatic breast cancer and is currently undergoing Phase III evaluation.