Targeting RSK Kinase with PMD-026: A Promising Strategy for Triple Negative Breast Cancer Therapy

Phoenix Molecular Designs has created PMD-026, a novel RSK inhibitor designed to combat triple negative breast cancer (TNBC). This compound was developed following the identification of RSK2 as a key growth promoter in TNBC, surpassing other breast cancer types. The RSK family, which intersects with the EGFR, MAPK, and PDK-1 pathways, is involved in the regulation of transcription and translation processes that foster the progression and spread of aggressive breast cancers. These kinases are also known to activate transcription factors like the estrogen receptor and YB-1, with the latter being linked to TNBC development.

PMD-026 has shown high selectivity for RSK isoforms in vitro and has demonstrated effectiveness against a diverse range of TNBC cell lines. It has also been shown to work in synergy with chemotherapy drugs such as paclitaxel and doxorubicin. The compound induces apoptosis, as evidenced by the upregulation of cleaved PARP, and modulates intracellular signaling pathways, notably reducing the expression of pYB-1.

In vivo studies have illustrated the efficacy of PMD-026 in mouse xenograft models of TNBC, with substantial tumor growth inhibition and regression. Notably, PMD-026 also showed significant efficacy when combined with paclitaxel in a patient-derived xenograft model. The compound has been observed to decrease pYB-1 expression in treated tumors, indicating consistent target engagement.

Importantly, PMD-026 did not exhibit cardiotoxicity, neutropenia, or ocular toxicity in GLP toxicology studies, distinguishing it from other kinase inhibitors in the MAPK pathway.

Additionally, a companion diagnostic has been developed, revealing that RSK2 is activated in the majority of TNBC cases. This development offers a potential Rx/Dx solution for TNBC, leveraging the functional dependency of the disease. PMD-026 represents a groundbreaking RSK inhibitor, offering a novel treatment avenue for TNBC patients in Phase 1/1b clinical trials.