The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Structural Biology

Background:

• MCL-1 is a key anti-apoptotic protein implicated in cancer.
• Thieno[2,3-d]pyrimidine scaffolds have emerged as promising inhibitors of MCL-1.

Purpose of the Study:

• To explore the impact of core structure modifications on the potency and properties of thieno[2,3-d]pyrimidine-based MCL-1 inhibitors.
• To identify novel chemical vectors and optimize lead compounds for potential clinical development.

Main Methods:

• Structure-based drug design utilizing X-ray crystallography.
• Synthesis and SAR (Structure-Activity Relationship) studies of thieno[2,3-d]pyrimidine analogues.
• In vitro biochemical and cellular assays to assess affinity and activity.
• In vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies in preclinical models.

Main Results:

• Core swapping strategies revealed a significant dependence of affinity and cellular activity on the heterocyclic core.
• Exploration of a novel vector led to the engagement of the MCL-1 deep-S2 pocket, though it resulted in an affinity plateau.
• Certain core-swapped analogues exhibited accelerated epimerization of atropisomers.
• The most potent analogues demonstrated robust in vivo PD response and tumor growth inhibition in efficacy studies.

Conclusions:

• Core structure is critical for optimizing MCL-1 inhibitor potency and pharmacological properties.
• Strategic modifications can modulate target engagement and overcome limitations like affinity plateaus.
• The identified lead compound warrants further investigation for its therapeutic potential in MCL-1-dependent cancers.