Reference Detail

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) 28	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 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	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
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
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 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
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
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
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 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
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 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
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
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 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