Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Selective inhibition of Positive Transcription Elongation Factor b/CDK9 is a promising cancer therapy strategy.
• Atuveciclib was the first selective CDK9 inhibitor in clinical development.

Purpose of the Study:

• To discover intravenously applicable CDK9 inhibitors with an improved therapeutic index.
• To identify a highly potent and selective clinical candidate for cancer treatment.

Main Methods:

• Lead optimization of CDK9 inhibitors starting from atuveciclib.
• Scaffold hopping strategies were employed.
• Preclinical evaluation in vitro and in vivo, including xenograft models.

Main Results:

• Discovery of VIP152, a potent and selective CDK9 inhibitor featuring a benzyl sulfoximine group.
• VIP152 demonstrated high efficacy and good tolerability in preclinical xenograft models.
• VIP152 exhibited promising long-term, durable monotherapy activity in clinical trials for double-hit diffuse large B-cell lymphoma.

Conclusions:

• VIP152 represents a promising clinical candidate for cancer therapy, particularly for specific B-cell lymphomas.
• The benzyl sulfoximine scaffold offers a novel structural basis for developing selective CDK9 inhibitors.
• VIP152 shows potential for durable monotherapy in patients with double-hit diffuse large B-cell lymphoma.