The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

PanKRAS Inhibitor

Geo Regions

PanKRAS Inhibitor

PF-07934040 is an investigational compound. Its safety and efficacy have not been established.

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Overview + Rationale

  • KRAS (Kirsten rat sarcoma viral oncogene homologue) is part of the RAS family, which includes NRAS (neuroblastoma) and HRAS (Harvey)1
  • The RAF-MEK-ERK pathway is the canonical downstream target of KRAS signalling2
  • KRAS is activated by guanine nucleotide exchange factors and interacts with effector proteins to activate downstream signaling pathways, thus regulating cell growth, survival, and proliferation. GTPase-activated proteins promote hydrolysis of KRAS and return KRAS to an inactive state1
  • KRAS is the most frequently mutated member of the RAS family and is the most common oncogenic gene driver in human cancers, including pancreatic, colorectal and lung cancers1,2
  • PF-07934040 is a panKRAS "ON/OFF" inhibitor with activity against wild-type (wt) KRAS, as well as major mutant isoforms. It has no activity against NRAS or HRAS
  • PF-07934040 showed binding to both OFF (GDP-bound) and ON (GTP-loaded) states of KRAS wt and mutants with very low binding affinities
  • PF-07934040 binds with >5000-fold selectivity for KRAS over HRAS/NRAS

Mechanism of Action

PF-07934040

PF-07934040 blocks binding of RAF-RBD to GTPgS-loaded KRAS mutants, suggesting that the MOA includes binding to the ON-state of KRAS and inhibition of RAF binding, potentially modulating downstream signaling

Stage of Development

Phase 1

Monotherapy and Combination

small icon representing Other/Multiple Cancer type
Advanced Solid Tumors
Phase 1 Monotherapy and Combination

CRC=colorectal cancer; ERK=extracellular signal-related kinases; GDP=guanosine diphosphate; GTP=guanosine-5’-triphosphate; GTP_ gamma_ S = guanosine 5'-O-[gamma-thio]triphosphate; MEK=mitogen-activated extracellular signal-regulated kinase; NRAS=neuroblastoma RAS; PDAC=pancreatic ductal adenocarcinoma; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma virus; RBD=Ras binding domain; SOS1=son of sevenless 1

REFERENCES: 1.Wang et al. Acta Pharmacologica Sinica. 2022. 43:2696–2708; 2.Huang et al. Sig Transduct Target Ther. 2021. 6, 386; 3.. Pfizer Inc., Data on file;  4. Pancholli, N. 2021 Molecular Targets The Latest Efforts to Overcome Resistance to KRAS an article published [date] on Cancer Research Catalyst, the American Association for Cancer Research’s official blog  https://www.aacr.org/blog/2021/10/20/molecular-targets-2021-the-latest-efforts-to-overcome-resistance-to-kras-inhibitors; Accessed July 30, 2024;  5. Leshchiner, Elizaveta S et al. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices.” Proceedings of the National Academy of Sciences of the United States of America vol. 112,6 (2015): 1761-6. doi:10.1073/pnas.1413185112; 6. Clinicaltrials.gov  https://clinicaltrials.gov/study/NCT06447662 Accessed July 30, 2024;