Undisclosed SHP2 PROTAC / Sino Biopharm - LARVOL DELTA

SHP2-ProTAC Unleashes Potent Antitumor Efficacy against KRAS-Mutant Pancreatic Cancer Free (AACRPanCa 2025) - "The AG regimen (nab-paclitaxel plus gemcitabine) remains the standard treatment for advanced and metastatic PDAC, offering a median survival of about [AL1] 8.5 months...Current FDA-approved KRAS inhibitors (AMG510 and MRTX-849) target KRAS-G12C, which represent merely 1-2% of PDAC cases...TRD209 maintained an IC50 of 17.3nM in AMG510-ressistent H358-G12C/Y96D double-mutant cell-line, while AMG510(KRAS-G12C inhibitor) and RMC-6236(pan-KRAS inhibitor) showed no efficacy at all...Our results indicated that TRD209, a novel SHP2-ProTAC, effectively inhibits the proliferation across diverse KRAS-mutant PDAC models, particularly efficacy against those harboring KRAS-G12D mutations. Moreover, it overcomes resistance to existing KRAS inhibitors and shows exceptional potency in neuroendocrine pancreatic tumors. These findings establish TRD209, a SHP2 degrader, as a promising therapeutic strategy for KRAS-mutant pancreatic cancer, potentially addressing the limitations of current..."

Clinical • Endocrine Cancer • Gastrointestinal Neuroendocrine Carcinoma • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

Revolutionizing cancer treatment with the first SHP2 PROTAC (AACR 2025) - "SHP2 inhibitors, like JAB3312, is limited to inhibiting phosphatase activity and evaluated in combination regimens rather than as standalone therapies...Mechanistic studies confirmed TRD209 acts via ubiquitin-proteasome pathway, as validated by TAK-243 and MG132 blockade assays...TDS0593 offer a novel strategy for the treatment of myeloid leukemia by correcting aberrant myeloid-biased differentiation of HSC/HSPC. This innovative approach aims to rectify the underlying dysregulation in hematopoietic differentiation processes, achieving efficacy in myeloid leukemia.TDS0593 reduces leukemic burden and promotes the restoration of HSC% of Myeloid cells in BM% of Myeloid cells in PBHSC/45.2+ in BMnaive48.72(39.47~52.37)40.16(37.27~43.06)0.00312(0.00257~0.004635)kras-mut mouse models + vehicle66.50(64.40~69.40)59.40(41.00~72.10)0.01079(0.007630~0.01500)kras-mut mouse models + TDS059354.07(47.60~63.20)38.32(29.10~51.30)0.005865(0.002350~0.009110)"

IO biomarker • Late-breaking abstract • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • KRAS • PD-1 • PTPRC