Inhibiting RSK suppresses cancer growth and inflammation
Ribosomal S6 kinases (RSK) are a family of proteins made up of RSK1-4 isoforms. RSK1 and RSK2 are the main isoforms found in cancer and they serve unique roles. RSK1 promotes the spread of cancer and blocks differentiation, whereas RSK2 protects cancer cells from death and promotes drug resistance through cell cycle slippage. RSK2 also binds to the estrogen receptor to drive the development of breast cancer, where its expression is associated with poor outcomes in patients.
As a pan-RSK inhibitor, PMD-026 is uniquely poised to address needs across the cancer spectrum.
PMD-026 is active against both solid tumors and hematological malignancies. While the inhibition of MAPK or PI3K is associated with a high incidence of rash and hyperglycemia, inhibiting RSK is not.
Our Phase 1 clinical trial showed a low incidence of rash and no hyperglycemia. In addition, PMD-026 stopped tumors from growing in 44% of breast cancer patients.
RSK2 also serves as a traceable biomarker for cancers that could benefit from PMD-026. Our Phase 1 clinical data revealed that RSK2 was highly expressed in 70% of the cases and that high RSK2 was also associated with 3x longer progression-free survival compared to low RSK2.
Breast cancer patients in our Phase 1 study who benefitted from PMD-026 had previously progressed on chemotherapy, hormone therapy, immunotherapies, antibody-drug conjugates, and/or targeted therapies such as CDK4/6 inhibitors.
PMD-026 is a robust strategy for breaking through CDK4/6i resistance
RSK signaling drives cancer growth and drug resistance. Targeting RSK leads to G2/M arrest and cancer cell death, which is a novel approach to overcoming resistance to many drugs, including CDK4/6 inhibitors. Other clinical assets are focused on G1/S inhibition which often becomes ineffective due to the multiple bypass mechanisms, and most lack a biomarker-driven approach.
PMD-026 blocks G2/M, offering an opportunity to overcome CDK4/6i resistance. Our biomarker-driven approach using RSK2 is highly targeted and thus tailor-made for patients.
RSK was undruggable until now; PMD-026 is the first orally available RSK kinase inhibitor.
We have overcome the chemistry challenge through precision mapping.
By leveraging computational modelling and state-of-the-art medicinal chemistry. PMD-026 is a highly selective inhibitor and an entirely new way to treat cancer. PMD-026 is designed to be taken orally, which is more convenient and less disruptive to patient’s lives.
