DP-9149 / Ono Pharmaceutical - LARVOL DELTA

A novel small molecule activator of the integrated stress response kinase GCN2 shows potent preclinical antitumor activity as monotherapy and in combination with standard of care agents (EORTC-NCI-AACR 2024) - "Additionally, robust tumor regressions were achieved in vivo when DP-9149 was combined with standard of care (SOC) anti-angiogenic therapies (cabozantinib, axitinib, or sunitinib) in renal cell carcinoma xenograft models. The combination of DP-9149 with a KRAS G12C inhibitor (sotorasib) in NSCLC xenograft models or with chemotherapy agents (gemcitabine or cisplatin) in a bladder cancer xenograft model also promoted robust tumor regressions in vivo. DP-9149 activates GCN2, which upregulates the ISR pathway and induces anti-tumoral effects in solid tumors in vitro and in vivo through the induction of an unresolved stress response. In particular, DP-9149 exhibited robust activity as a single agent and in combination with SOC agents in renal cell, bladder, and KRAS-mutant cancers in vivo."

Combination therapy • Monotherapy • Preclinical • Bladder Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ATF4 • EIF2A • EIF2S1 • KRAS

DP-9149, an investigational small molecule modulator of the Integrated Stress Response kinase GCN2, pre-clinically causes solid tumor growth inhibition as a single agent and regression in combination with standard of care agents (AACR 2023) - "The ISR is a targetable vulnerability in oncogene addicted solid tumors. Upregulating the ISR by paradoxical activation of the ISR family member kinase, GCN2, by DP-9149 can be leveraged as a novel mechanism to cause anti-tumoral effects in solid tumors in vitro and in vivo, likely through the induction of an unresolved stress response. In particular, DP-9149 exhibited robust activity in RAS mutant cancers and in VHL-mutant renal cancers as a single agent and in combination with SOC agents in vivo."

Combination therapy • Preclinical • Fibrosarcoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • ATF4 • CASP3 • CASP7 • VHL

Deciphera Pharmaceuticals Announces Eight Presentations Highlighting Discovery Research Programs at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Businesswire) - "...'At the upcoming AACR meeting, we look forward to presenting preclinical data supporting our next Investigational New Drug (IND) candidate, DCC-3084, a potential best-in-class pan-RAF inhibitor that broadly inhibits Class I, II, and III BRAF mutations, BRAF fusions, and BRAF/CRAF heterodimers. In addition, we will present preclinical data on our ULK inhibitor, DCC-3116, in combination with QINLOCK in gastrointestinal stromal tumor (GIST) and in combination with encorafenib and cetuximab in colorectal cancer that strongly support two new dose escalation combination studies that we expect to initiate in the second half of this year'....'We are excited to share initial preclinical data on two new programs, GCN2 and PERK, two novel targets focused on the integrated stress response'...New pan-kit development candidate DCC-3009 for GIST demonstrates potential best-in-class profile with broad coverage of KIT mutations with high selectivity."

New trial • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor