Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic protein frequently upregulated in human cancers.
• Mcl-1 overexpression correlates with high tumor grade, poor patient survival, and chemoresistance.
• Targeting Mcl-1 offers a potential therapeutic strategy for various malignancies.

Purpose of the Study:

• To discover and develop a selective small molecule inhibitor of Mcl-1.
• To optimize a lead compound for improved target affinity, cellular potency, and selectivity.
• To evaluate the preclinical efficacy and drug-like properties of the Mcl-1 inhibitor.

Main Methods:

• Structure-guided optimization of a fragment-derived lead compound.
• Assessment of target affinity, cellular potency, and selectivity against Bcl-2 family proteins.
• Establishment of predictive pharmacodynamic (PD) markers for Mcl-1 inhibition.
• Evaluation of in vitro cell killing and in vivo tumor regression in Mcl-1 dependent cancer models.

Main Results:

• Discovery of clinical candidate S64315, a potent and selective Mcl-1 inhibitor.
• Achieved a 3-log improvement in target affinity and cellular potency through optimization.
• Demonstrated high selectivity for Mcl-1 over other Bcl-2 family members due to hindered biaryl rotation.
• Established predictive PD markers and showed efficient Mcl-1 inhibition, leading to tumor regression.
• The preclinical candidate possesses favorable drug-like properties.

Conclusions:

• S64315 is a potent and selective Mcl-1 inhibitor with promising preclinical data.
• The compound demonstrates efficacy in Mcl-1 dependent cancer models, including tumor regression.
• S64315 has favorable drug-like properties, supporting its advancement into clinical trials.
• Targeting Mcl-1 with selective inhibitors like S64315 represents a viable therapeutic approach for cancer treatment.