Two Small Molecules, ZCL278 and AZA197 Show Promise in Influencing Protein Interactions Involving the Ras-Related Protein Cell division cycle 42 [Cdc42] to Modulate Its Oncogenic Potential

Abstract

Cdc42 is a member of the Rho subfamily of Ras-related proteins, which were among the first oncogenic proteins to be identified as playing a significant role in a variety of cellular events [Barbacaid, 1987, Ann. Rev. Biochem]. Equally important, Protein-Protein Interactions [PPIs] involving Cdc42 continue to highlight the role of Ras-related proteins' relevance to cancer. As these proteins have been considered incapable of being "druggable", due to a perceived lack of binding surface [s] that are amenable to small molecule targeting, there remains limited development of therapies to tackle diseased states caused by Cdc42-stimulated hyperactivity. Thusly, it has become important to characterize molecular details, including dynamics, of PPIs involving Cdc42 that may lend themselves as potential targets for therapeutic approaches. Recently, two small molecules, ZCL278 and AZA197, have shown promise in directly targeting Cdc42 to influence PPIs that are capable of causing Cdc42-stimulated abnormal signaling. In this editorial, we highlight recent studies that show case how these two small molecules may influence Cdc42-protein interactions.

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“…Another potential inhibitor of Cdc42 with therapeutic applications in cancer is ZCL278, a 4-bromine-2-chlorophenol derivative that disrupts the joining between Cdc42 and intersectin (ITSN), which is a Cdc42-specific GEF enzyme, leading to inhibiting the activation of this small GTPase [139,140]. ZCL278 presents promising properties for being used in cancer therapy, such as a high membrane permeability and low toxicity for non-carcinogenic cells [137].…”

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“…However, the lack of binding surface for small molecule targeting of Protein-Protein Interactions (PPIs) involving Cdc42 is yet to be revealed. 95 The two small molecules, ZCL278, and AZA197 target Cdc42 to influence PPIs. They can inhibit Cdc42 and suppress proliferative and pro-survival signalling pathways through PAK1-ERK signalling.…”

“…They directly block the replication of this virus in cell culture. However, the lack of binding surface for small molecule targeting of Protein–Protein Interactions (PPIs) involving Cdc42 is yet to be revealed 95 . The two small molecules, ZCL278, and AZA197 target Cdc42 to influence PPIs.…”