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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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IHMT-RAF-128 | IHMT-RAF-128 | 13 | 0 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 |
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 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 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 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 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 |
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 |
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 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 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 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 |