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Ref Type Journal Article
PMID (37164118)
Authors Wang A, Liu J, Li X, Zou F, Qi Z, Qi S, Liu Q, Wang Z, Cao J, Jiang Z, Wang B, Ge J, Wang L, Wang W, Liu J, Liu Q
Title Discovery of a highly potent pan-RAF inhibitor IHMT-RAF-128 for cancer treatment.
Journal Vol Issue Date Pages Journal Short Title
European journal of pharmacology 952 2023 Aug 05 175752 Eur J Pharmacol
URL
Abstract Text Although rat sarcoma viral oncogene homolog (RAS) mutations occur in about 30% of solid tumors, targeting RAS mutations other than KRAS-G12C is still challenging. As an alternative approach, developing inhibitors targeting RAF, the downstream effector of RAS signaling, is currently one of the main strategies for cancer therapy. Selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-V600E inhibitors Vemurafenib, Encorafenib, and Dabrafenib have been approved by FDA and received remarkable clinical responses, but these drugs are ineffective against RAS mutant tumors due to limited inhibition on dimerized RAF. In this study, we developed a highly potent pan-RAF inhibitor, IHMT-RAF-128, which exhibited similarly high efficacies in inhibiting both partners of the RAF dimer, and showed potent anti-tumor efficacy against a variety of cancer cells harboring either RAF or RAS mutations, especially Adagrasib and Sotorasib (AMG510) resistant-KRAS-G12C secondary mutations, such as KRAS-G12C-Y96C and KRAS-G12C-H95Q. In addition, IHMT-RAF-128 showed excellent pharmacokinetic profile (PK), and the bioavailability in mice and rats were 63.9%, and 144.1%, respectively. Furthermore, IHMT-RAF-128 exhibited potent anti-tumor efficacy on xenograft mouse tumor models in a dose-dependent manner without any obvious toxicities. Together, these results support further investigation of IHMT-RAF-128 as a potential clinical drug candidate for the treatment of cancer patients with RAF or RAS mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IHMT-RAF-128 IHMT-RAF-128 13 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
IHMT-RAF-128 IHMTRAF-128|IHMTRAF 128|IHMTRAF128|IHMTRAF 128 RAF Inhibitor (Pan) 29 IHMT-RAF-128 is a pan-RAF inhibitor, which potentially induces cell cycle arrest and apoptosis and decreases tumor growth (PMID: 37164118).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS A146T acute lymphoblastic leukemia sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in an acute lymphoblastic leukemia cell line harboring NRAS A146T in culture (PMID: 37164118). 37164118
BRAF G466V lung non-small cell carcinoma sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in a non-small cell lung cancer cell line harboring BRAF G466V in culture (PMID: 37164118). 37164118
NRAS G12D Advanced Solid Tumor sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation of a cell line expressing NRAS G12D in culture (PMID: 37164118). 37164118
BRAF V600E colon cancer sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in a colon cancer cell line harboring BRAF V600E in culture (PMID: 37164118). 37164118
BRAF V487_P492delinsA pancreatic cancer sensitive IHMT-RAF-128 Preclinical - Cell line xenograft Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in a pancreatic cancer cell line harboring BRAF V487_P492delinsA in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37164118). 37164118
BRAF K601E Advanced Solid Tumor sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation of a cell line expressing BRAF K601E in culture (PMID: 37164118). 37164118
NRAS Q61K thyroid cancer sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in a thyroid cancer cell line harboring NRAS Q61K in culture (PMID: 37164118). 37164118
BRAF V600E Advanced Solid Tumor sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation of a cell line expressing BRAF V600E in culture (PMID: 37164118). 37164118
NRAS G12S acute lymphoblastic leukemia sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in an acute lymphoblastic leukemia cell line harboring NRAS G12S in culture (PMID: 37164118). 37164118
BRAF V487_P492delinsA pancreatic cancer resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a pancreatic cancer cell line harboring BRAF V487_P492delinsA was resistant to Zelboraf (vemurafenib) in culture (PMID: 37164118). 37164118
BRAF G469A Advanced Solid Tumor sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation of a cell line expressing BRAF G469A in culture (PMID: 37164118). 37164118
BRAF V600E melanoma sensitive IHMT-RAF-128 Preclinical - Cell line xenograft Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation and induced cell cycle arrest and apoptosis in melanoma cell lines harboring BRAF V600E in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37164118). 37164118
BRAF L597V NRAS Q61K lung non-small cell carcinoma sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in a non-small cell lung cancer cell line harboring NRAS Q61K and BRAF L597V in culture (PMID: 37164118). 37164118
HRAS Q61L esophageal cancer sensitive IHMT-RAF-128 Preclinical - Cell culture Actionable In a preclinical study, IHMT-RAF-128 inhibited proliferation in an esophageal cancer cell line harboring HRAS Q61L in culture (PMID: 37164118). 37164118