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Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor
Zoltan Szlavik1, Marton Csekei1, Attila Paczal1
1Servier Research Institute of Medicinal Chemistry, Záhony u. 7, H-1031 Budapest, Hungary.
Abstract:
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
Insights
A new drug candidate, S64315, selectively inhibits Mcl-1, a protein linked to cancer growth and drug resistance. This promising therapy shows potential for treating Mcl-1 dependent cancers.
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.
