SW-3431 / Rappta Therapeutics, EMD Serono - LARVOL DELTA

Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML. (PubMed, JCI Insight) - "Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

Discovery of RPT04402, a first-in-class molecular glue activator with potent and selective anti-tumor activity in PPP2R1A mutant cancers (EORTC-NCI-AACR 2026) - "Abstract will be available as of 4 November (with consent of the author)"

Oncology • PPP2R1A

A PP2A molecular glue restores heterotrimer formation for the treatment of high-grade uterine cancers [WITHDRAWN] (AACR 2025) - "For the high-grade subtypes, surgery remains the mainstay of treatment, and while the approval of the combination of Pembrolizumab and Lenvatinib is a promising treatment strategy, there is only a 50% response rate in women with recurrent disease, highlighting the need for additional therapeutic options...The molecule RPT04402 promoted B56α heterotrimerization to the AαP179R and AαS256F mutant scaffolds...This molecule has undergone preclinical toxicology studies and is well tolerated in multiple species. Combined, these data demonstrate that PP2A molecular glues are a promising novel therapy for PPP2R1A mutant uterine cancer patients and represent the first small molecule approach targeting a driver of this aggressive disease."

Carcinosarcoma • Endometrial Serous Adenocarcinoma • Oncology • Sarcoma • Solid Tumor • Uterine Cancer • PPP2R1A • TP53

Discovery of SW-3431, a first-in-classmolecular glue activator with potent and selective anti-tumor activity in PPP2R1A mutant cancers (AACR-NCI-EORTC 2025) - "Importantly, this activity was abrogated upon knockout of B56α demonstrating a high degree of target specificity to this specific PP2A heterotrimer. Combined, these data demonstrate that PP2A molecular glues are a promising novel therapy for PPP2R1A mutant uterine cancer patients and represent the first small molecule approach targeting a driver of this aggressive disease."

Endometrial Cancer • Endometrial Serous Adenocarcinoma • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Uterine Cancer • PPP2R1A • TP53

A PP2A molecular glue overcomes ras/mapk inhibitor resistance in kras-mutant non-small cell lung cancer. (PubMed, J Clin Invest) - "We developed RPT04402, a PP2A molecular glue that selectively stabilizes PP2A-B56α heterotrimers...In mouse xenografts, this combination induced tumor regressions, extended median survival, and delayed the onset of treatment resistance. These findings highlight that promoting PP2A stabilization and RAS/MAPK inhibition presents a promising therapeutic strategy to improve treatment outcomes and overcome resistance in metastatic KRAS-mutant NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • KRAS

Rappta Therapeutics enters into a global license agreement with SpringWorks Therapeutics for a pre-clinical first-in-class molecular glue targeting PP2A (PRNewswire) - "Rappta Therapeutics...announces an exclusive global license agreement with SpringWorks Therapeutics ('SpringWorks') for RPT04402, a first-in-class molecular glue of specific Protein Phosphatase 2A (PP2A) complexes....In pre-clinical models of PP2A mutant uterine cancer, RPT0402 achieved rapid, deep and durable tumor regressions at as monotherapy. Under the exclusive license agreement, SpringWorks Therapeutics will be responsible for global development and commercialization of RPT04402. SpringWorks has paid Rappta $13 million upfront, and Rappta is also eligible to receive further clinical, regulatory and commercial milestone payments, and tiered single-digit royalties on net sales. SpringWorks expects to file an Investigational New Drug (IND) application for RPT04402 by the end of 2025."

IND • Licensing / partnership • Uterine Cancer

SpringWorks Therapeutics Reports Preliminary Fourth Quarter and Full Year 2024 Financial Results and Provides Business Updates at 43rd Annual J.P. Morgan Healthcare Conference (GlobeNewswire) - "Emerging Pipeline: SpringWorks expects additional data to be presented by MapKure from the brimarafenib monotherapy trial in the second half of 2025. Continue enrolling patients in Phase 1 trial of SW-682 in Hippo-mutant solid tumors. File an Investigational New Drug (IND) application for SW-3431 by the end of 2025."

Enrollment status • IND • P1 data • Oncology • Solid Tumor