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Ref Type Journal Article
PMID (37808191)
Authors Liu Y, Cheng Y, Huang G, Xia X, Wang X, Tian H
Title Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor.
Journal Vol Issue Date Pages Journal Short Title
Frontiers in pharmacology 14 2023 1271268 Front Pharmacol
URL
Abstract Text Background: Aberrant activation of RAS-RAF-MEK-ERK signaling pathway has been implicated in more than one-third of all malignancies. MEK inhibitors are promising therapeutic approaches to target this signaling pathway. Though four MEK inhibitors have been approved by FDA, these compounds possess either limited efficacy or unfavorable PK profiles with toxicity issues, hindering their broadly application in clinic. Our efforts were focused on the design and development of a novel MEK inhibitor, which subsequently led to the discovery of tunlametinib. Methods: This study verified the superiority of tunlametinib over the current MEK inhibitors in preclinical studies. The protein kinase selectivity activity of tunlametinib was evaluated against 77 kinases. Anti-proliferation activity was analyzed using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) or (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. ERK and phospho-ERK levels were evaluated by Western blot analysis. Flow cytometry analysis was employed to investigate cell cycle and arrest. Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) models were used to evaluate the tumor growth inhibition. The efficacy of tunlametinib as monotherapy treatment was evaluated in KRAS/BRAF mutant or wild type xenograft model. Furthermore, the combination studies of tunlametinib with BRAF/KRASG12C/SHP2 inhibitors or chemotherapeutic agent were conducted by using the cell proliferation assay in vitro and xenograft models in vivo. Results:In vitro, tunlametinib demonstrated high selectivity with approximately 19-fold greater potency against MEK kinase than MEK162, and nearly 10-100-fold greater potency against RAS/RAF mutant cell lines than AZD6244. In vivo, tunlametinib resulted in dramatic tumor suppression and profound inhibition of ERK phosphorylation in tumor tissue. Mechanistic study revealed that tunlametinib induced cell cycle arrest at G0/G1 phase and apoptosis of cells in a dose-proportional manner. In addition, tunlametinib demonstrated a favorable pharmacokinetic profile with dose-proportionality and good oral bioavailability, with minimal drug exposure accumulation. Furthermore, tunlametinib combined with BRAF/KRASG12C/SHP2 inhibitors or docetaxel showed synergistically enhanced response and marked tumor inhibition. Conclusion: Tunlametinib exhibited a promising approach for treating RAS/RAF mutant cancers alone or as combination therapies, supporting the evaluation in clinical trials. Currently, the first-in-human phase 1 study and pivotal clinical trial of tunlametinib as monotherapy have been completed and pivotal trials as combination therapy are ongoing.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
BRAF V600E melanoma sensitive Tunlametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Tunlametinib (HL-085) inhibited viability and induced cell cycle arrest in melanoma cell lines harboring BRAF V600E in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 37808191). 37808191
BRAF V600E melanoma sensitive Tunlametinib + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of Tunlametinib (HL-085) and Zelboraf (vemurafenib) synergistically inhibited proliferation of a melanoma cell line harboring BRAF V600E in culture, and synergistically inhibited tumor growth in a cell line xenograft model (PMID: 37808191). 37808191
BRAF V600E colorectal cancer sensitive Tunlametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Tunlametinib (HL-085) inhibited viability of a colorectal cancer cell line harboring BRAF V600E in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37808191). 37808191
BRAF V600E colorectal cancer sensitive Tunlametinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of Tunlametinib (HL-085) and Zelboraf (vemurafenib) synergistically inhibited proliferation of a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 37808191). 37808191