Abstract P3-10-10: PMD-026, a first-in-class oral p90 ribosomal S6 kinase (RSK) inhibitor for triple negative breast cancer (TNBC)

In an effort to find novel drug targets for triple negative breast cancer (TNBC), Phoenix Molecular Designs (PhoenixMD) has developed PMD-026, the first orally bioavailable small molecule inhibitor targeting RSK (p90 ribosomal S6 kinase). RSK2 was identified as the most important kinase for the growth of TNBC compared to other breast cancer subtypes through siRNA functional screens. The RSK family of kinases are a convergence point in the EGFR, MAPK and PDK-1 pathways. They are implicated in the regulation of transcriptional and translational signalling, which promotes the growth and metastasis of invasive breast cancers. In breast cancer, they activate a number of transcription factors through phosphorylation events, including the estrogen receptor and the Y-box binding protein-1 (YB-1), the latter of which has been shown to drive the development of TNBC in mice. RSK2 is an ideal molecular target due to broad spectrum tumor dependency, despite the known heterogeneity within TNBC. PMD-026 demonstrates high specificity for the four RSK isoforms in vitro (IC50 0.7 -2 nM), with good selectivity in a kinome-wide counter screen. PMD-026 is active across a heterogeneous panel of TNBC cell lines in vitro under anchorage independent (IC50 0.2 - 6.2 µM) and dependent growth conditions (IC50 1.8 - 8.4 µM). Further, it synergizes with chemotherapies such as paclitaxel and doxorubicin in breast cancer cell lines in vitro. PMD-026 induces apoptosis, as indicated by increased expression of cleaved PARP, and induces changes in intracellular pathway signaling, with consistent dose-dependent decreased expression of pYB-1, a downstream target of RSK. PMD-026 demonstrates in vivo efficacy in several mouse xenograft tumor models of TNBC, when administered as a single agent, with significant tumor growth inhibition (TGI) and regression measured in MDA-MB-231 (72% TGI, p ≤ 0.001) and MDA-MB-468 xenografts (73% regression, p ≤ 0.001), respectively. PMD-026 also inhibits the growth of a PDx TNBC tumor model in vivo in combination with paclitaxel (80% TGI, p ≤ 0.001). A dose-dependent decrease in pYB-1 expression in the treated tumors is observed, indicative of consistent target engagement in vivo. Through these studies, we are able to show that PMD-026 is active across tumors models that have mutant BRCA1/2 and/or express PDL-1, providing a potential alternative treatment strategy when therapies such as PARP inhibitors or TECENTRIQ fail. In GLP toxicology studies, PMD-026 did not cause any apparent cardiotoxicity, neutropenia or ocular toxicity in mice and dogs, setting RSK inhibitors apart from other inhibitors targeting kinases in the MAPK signaling pathway. Lastly, we developed a companion diagnostic (CDx) and determined that RSK2 is activated in 85% of TNBC. Taken together, we have an Rx/Dx solution for TNBC predicated on functional dependency. PMD-026 is a first-in-class RSK inhibitor purpose built for the treatment of TNBC, which provides a unique opportunity to deliver a new treatment option for patients in our Phase1/1b clinical trial. Citation Format: Sandra E. Dunn, Aarthi Jayanthan, My-my Huynh, Erik Flahive, Mary Rose Pambid, Andrew Dorr, Gerrit Los. PMD-026, a first-in-class oral p90 ribosomal S6 kinase (RSK) inhibitor for triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-10.