BI-2493 / Boehringer Ingelheim - LARVOL DELTA

An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer. (PubMed, Sci Transl Med) - "Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC)...In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AMPK • CD8 • KRAS • STK11

Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy. (PubMed, J Med Chem) - "Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization."

Journal • Preclinical • Oncology • HRAS • KRAS

Oral and selective ribonucleotide reductase (RNR) inhibitor, BBI-825, suppresses acquired resistance to mutant-specific, pan, and multi-RAS targeting inhibitors (AACR 2025) - P1 | "In this preclinical study, we sought to understand whether BBI-825 broadly antagonizes acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of tumor models.We tested the ability of BBI-825 to prevent or delay development of acquired resistance to RAS targeting in a panel of KRASG12D/C/V driven tumor cell lines when used in combination with mutant specific KRASG12D (MRTX-1133, RMC-9805), KRASG12C (adagrasib, sotorasib), pan-KRAS (BI-2493), and multi-RAS (RMC-6236) inhibitors. Overall, we found that BBI-825 successfully antagonizes the development of acquired resistance to mutant-specific, pan, and multi-RAS inhibitors in a range of preclinical models. These findings support clinical investigation of BBI-825 in combination with mutant-specific, pan, and multi-RAS inhibitors to prevent or delay resistance and prolong duration of response."

Preclinical • Oncology • Solid Tumor • KRAS

Assessing KRAS inhibitors in pancreatic cancer using multiomics and advanced imaging to identify novel treatment co-targets (LCC 2025) - "For example, Mirati's G12D KRAS inhibitor, MRTX1133, can cause a >50% decrease in tumour burden in mouse models of PC4. More broadly, pan-KRAS inhibitors can act on all KRAS mutations, such as RMC-6236 (Revolution Medicines) and BI-2493 (Boehringer Ingelheim)5,6...Future work will also include assessment of our new putative co-targets using intravital (in vivo) imaging and biosensor technology. Overall, we aim to find new targets for combination treatment to improve the efficacy and durability of these first-in-class KRAS inhibitors."

Metastases • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification. (PubMed, Mol Cancer Ther) - "KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent anti-tumor activity in vitro and in vivo in KRAS wild-type amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacological inhibition of KRAS shows anti-tumor activity in preclinical models of cancer with KRAS wild-type amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration."

Journal • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor • KRAS