Development of PROTAC degrader probe of CDK4/6 based on DCAF16

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its high malignancy and limited effective treatments.
• Aberrant cell cycle regulation, particularly involving cyclin-dependent kinases 4/6 (CDK4/6), is a hallmark of many cancers, making CDK4/6 a validated therapeutic target.
• DCAF16 E3 ligase, localized in the nucleus, presents an opportunity for targeted protein degradation strategies.

Purpose of the Study:

• To design and synthesize novel DCAF16-based degraders targeting CDK4/6 for potential TNBC treatment.
• To evaluate the efficacy and safety profile of these novel compounds in preclinical models.

Main Methods:

• A series of DCAF16-based CDK4/6 degraders were designed and synthesized by conjugating Palbociclib with a DCAF16 E3 ligase ligand (KB02) via various linkers.
• Compound A4 was selected for further evaluation based on its inhibitory activity against CDK4/6.
• In vitro assays assessed CDK4/6 protein levels in MDA-MB-231 cells, and in vivo studies utilized MDA-MB-231 xenograft models.

Main Results:

• Compound A4 demonstrated potent inhibition of CDK4/6 and dose- and time-dependent reduction of CDK4/6 protein levels in MDA-MB-231 TNBC cells.
• A4 exhibited significantly lower toxicity in normal cells compared to Palbociclib (7-fold reduction).
• In vivo studies showed that A4 has therapeutic potential in MDA-MB-231 xenograft models.

Conclusions:

• The novel DCAF16-based CDK4/6 degrader, compound A4, shows promising efficacy and an improved safety profile for TNBC treatment.
• A4 warrants further investigation as a potential therapeutic agent for triple-negative breast cancer.