PES-Cl

PES-Cl is a small molecule inhibitor of the heat shock protein 70 (HSP70) and a potent inhibitor of autophagy. It is a chlorinated analogue of phenylethynesulfonamide (PES) with significantly enhanced potency (approximately 10-fold lower IC50) and improved ability to inhibit autophagy compared to its parent compound. PES-Cl binds specifically to the C-terminal helical 'lid' domain of HSP70, which is abundantly expressed in tumor cells and stabilizes lysosomal membranes. By inhibiting HSP70, PES-Cl disrupts the function of the HSP70/HSC70 co-chaperone system, leading to the degradation of HSP90 client proteins such as HER2, AKT, and CDK4. Additionally, it has been shown to impair the activity of the Anaphase Promoting Complex/Cyclosome (APC/C), inducing G2/M cell cycle arrest. In preclinical studies, PES-Cl demonstrated efficacy against melanoma (including BRAF-inhibitor resistant strains) and B-cell lymphoma with minimal toxicity to normal cells.