KRAS multi-inhibitor
A pan-KRAS inhibitor directly targeting GDP-KRAS
BI 3706674: KRAS multi-inhibitor*
Our KRAS multi-inhibitor (BI 3706674) is a novel, potent and orally available small molecule inhibitor of the KRAS oncogene. This KRAS multi-inhibitor binds non-covalently to wild-type (wt) KRAS and to multiple KRAS mutant alleles, including KRASG12V, in the GDP-bound state, and blocks downstream oncogenic signaling.1
Clinical trial (monotherapy): Our KRAS multi-inhibitor is currently being investigated in a Phase I trial in patients with unresectable metastatic solid tumors including KRAS wild type amplified gastric, esophageal, and gastroesophageal junction adenocarcinoma or unresectable metastatic pancreatic ductal adenocarcinoma with KRAS G12V mutation.2
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
Role of KRAS
KRAS is one of the most frequently mutated oncogenes with high prevalence of alterations in pancreatic, colorectal and non-small cell lung tumors.3,4 KRAS functions as a molecular switch, existing in two states: the guanosine diphosphate-(GDP-)bound ‘off’ state, or the guanosine triphosphate-(GTP-)bound ‘on’ state. Active KRAS–GTP activates downstream effector pathways, including the RAF/MEK/ERK signaling pathway that regulates gene expression and prevents apoptosis.2,5
About KRAS multi-inhibitor
Mechanism of action
The KRAS multi-inhibitor is a non-covalent inhibitor that binds to the KRAS protein in its inactive form and locks KRAS in its inactive state, thus inhibiting the interaction between the KRAS protein and SOS1/SOS2 GEFs, blocking proliferation and causing tumor cell apoptosis.1
Clinical development
BI 3706674, a KRAS multi-inhibitor, is currently undergoing clinical investigation as a monotherapy in patients with unresectable metastatic KRAS wild type amplified and KRAS G12V mutated solid tumors including gastric, esophageal, and gastroesophageal junction adenocarcinoma, and PDAC, respectively.2
KRAS multi-inhibitor clinical trial
| Trial number | Phase | Treatment | Patient population | Status |
|---|---|---|---|---|
NCT06056024 (1512-0001)2 | I | BI 3706674 monotherapy | Unresectable metastatic KRAS wild type amplified gastric, esophageal, and gastroesophageal junction adenocarcinoma | Recruiting |
KRAS, Kristen Rat Sarcoma viral oncogene.
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Peng D, et al. Mol Cancer Ther. 2023;22(12_Supplement):A087
ClinicalTrials.gov. NCT06056024. https://clinicaltrials.gov/study/NCT06056024 (Accessed: February 2024
Hofmann MH, et al. Cancer Discov. 2021;11:142–157.
Hofmann MH, et al. Cancer Discov. 2022;12:924-937.
Evelyn CR, et al. Chem Biol. 2014;21:1618‒1628.