Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B‑Cell Lymphoma

The “magic methyl effect” has facilitated the successful development of numerous pharmaceutical compounds. During the development of HsClpP activators, we found that incorporating methyl groups into the bicyclic imipridone scaffolds significantly enhanced the activator activity at the enzymatic level. Further structure–activity relationship studies led to the identification of a highly promising compound, CLPP-2068, which exhibited an EC50 value of 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated that the introduction of methyl groups facilitated the formation of additional CH–π interactions between CLPP-2068 and HsClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that CLPP-2068 exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based HsClpP activators. Collectively, CLPP-2068, developed using the magic methylation strategy, holds potential as a therapeutic agent for the treatment of diffuse large B-cell lymphoma, thereby expanding the clinical indications for HsClpP activators.