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Chemical Structure| 934660-93-2 Chemical Structure| 934660-93-2

Structure of Cobimetinib
CAS No.: 934660-93-2

Chemical Structure| 934660-93-2

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Cobimetinib (GDC-0973, RG7420) is a potent, selective, oral MEK1 inhibitor with an IC50 of 4.2 nM for MEK1.

Synonyms: XL518; GDC-0973; RG-7420

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Zhao, Kun ; Zhao, Qi ; Dai, Xinzhi ; Wen, Xue ; Luo, Xing ; Duan, Yi , et al.

Abstract: Mitogen-activated protein kinase inhibitors (MAPKi) were the first line drugs for advanced melanoma patients with BRAF mutation. Targeted therapies have significant therapeutic effects; however, drug resistance hinders their long-term efficacy. Therefore, the development of new therapeutic strategies against MAPKi resistance is critical. Our previous results showed that MAPKi promote feedback activation of STAT3 signaling in BRAF-mutated cancer cells. Studies have shown that alantolactone inhibited the activation of STAT3 in a variety of tumor cells. Our results confirmed that alantolactone suppressed cell proliferation and promoted apoptosis by inhibiting STAT3 feedback activation induced by MAPKi and downregulating the expression of downstream Oct4 and Sox2. The inhibitory effect of alantolactone combined with a MAPKi on melanoma cells was significantly stronger than that on normal cells. In vivo and in vitro experiments showed that combination treatment was effective against drug-resistant melanomas. Our research indicates a potential novel combination therapy (alantolactone and MAPKi) for patients with BRAF-mutated melanoma.

Keywords: Alantolactone ; STAT3 ; MAPK pathway ; BRAF ; Melanoma ; Drug resistance

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Zhao, Kun ; Dai, Qiong ; Wu, Junli ; Wei, Zhang ; Duan, Yi ; Chen, Bo

Abstract: Background: BRAF and MEK inhibitors significantly prolonged the progression-free survival of patients with BRAF mutant melanoma, but their long-term efficacy was limited by drug resistance. Our previous studies found that targeted inhibition of the mitogen-activated protein kinases (MAPK) pathway promotes the activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in BRAF-mutant melanoma cells. Whether dual inhibition of MAPK and JAK2/STAT3 pathways can reverse drug resistance in melanoma remains unclear. Methods: This study verified whether morusin could enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma by inhibiting the feedback activation of STAT3 at the cellular and animal levels. Results: We demonstrated that morusin could enhance the inhibitory effect of MAPK pathway inhibitors on BRAF mutant melanoma cells by inhibiting the feedback activation of the STAT3/SOX2 pathway. Moreover, our study showed morusin combined with MAPK pathway inhibitors specifically inhibited BRAF-mutant melanoma cells to a greater extent than wild-type cells. Our results also showed that the combination of morusin and BRAF inhibitors could jointly inhibit BRAF mutant melanoma in vivo. Finally, our experiment also revealed that the combination therapy of morusin and MAPK pathway inhibitors jointly inhibited drug-resistant melanoma in vitro and in vivo. Conclusion: Our results suggested that the combination of morusin and MAPK pathway inhibitors may be a more effective treatment strategy for BRAF-mutant melanoma than MAPK pathway inhibitors alone.

Keywords: Morusin ; MAPK pathway ; BRAF mutation ; STAT3 ; Melanoma

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Alternative Products

Product Details of Cobimetinib

CAS No. :934660-93-2
Formula : C21H21F3IN3O2
M.W : 531.31
SMILES Code : O=C(C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F)N3CC([C@H]4NCCCC4)(O)C3
Synonyms :
XL518; GDC-0973; RG-7420
MDL No. :MFCD22124461

Safety of Cobimetinib

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of Cobimetinib

MAPK

Isoform Comparison

Biological Activity

Target
  • MEK1

    MEK1, IC50:4.2 nM

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT05125471 Arteriovenous Malformations (E... More >>xtracranial) Less << PHASE2 RECRUITING 2025-12-26 Arkansas Children's Hospital, ... More >>Little Rock, Arkansas, 72202, United States Less <<
NCT04079179 Langerhan's Cell Histiocytosis... More >>|Juvenile Xanthogranuloma|Erdheim-Chester Disease|Rosai Dorfman Disease|Neuro-Degenerative Disease|Histiocytic Sarcoma|Histiocytic Disorders, Malignant Less << PHASE2 RECRUITING 2025-12-29 Phoenix Children's Hospital, P... More >>hoenix, Arizona, 85016, United States|Arkansas Children's Hospital, Little Rock, Arkansas, 72202, United States|Children's Hospital of Orange County, Orange, California, 92868, United States|Children's National Hospital, Washington, District of Columbia, 20010, United States|John Hopkins University School of Medicine, Baltimore, Maryland, 21287, United States|Dana Farber Cancer Institute, Boston Children's, Boston, Massachusetts, 02215, United States|Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States|NACHO Consortium, Memphis, Tennessee, 38105, United States|Children's Medical Center- UTSW, Dallas, Texas, 75235, United States|Texas Children's Hospital, Houston, Texas, 77030, United States|University of Wisconsin-American Family Children's Hospital, Madison, Wisconsin, 53792, United States Less <<
NCT01711762 Healthy Volunteer PHASE1 COMPLETED 2025-09-12 Madison, Wisconsin, 53704, Uni... More >>ted States Less <<
NCT02639546 Solid Tumors PHASE1|PHASE2 COMPLETED 2021-07-21 Arkansas Children'S Hospital, ... More >>Little Rock, Arkansas, 72202, United States|Arnold Palmer Hosp-Children, Orlando, Florida, 32806, United States|Dana Farber Cancer Institute, Boston, Massachusetts, 02215, United States|Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States|University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, United States|H?pital de la Timone, Oncologie Pédiatrique, Marseille, 13385, France|Institut Curie, Oncologie Pédiatrique, Paris, 75231, France|Institut Gustave Roussy; Service Pediatrique, Villejuif, 94805, France|Universitaetsklinikum Muenster, Muenster, 48149, Germany|Schneider Children's Medical Center, Petach-Tikva, 49100, Israel|Fondazione IRCCS Istituto Nazionale dei Tumori; Struttura Complessa di Pediatria Oncologica, Milano, Lombardia, 20133, Italy|Hospital Universitari Vall d'Hebron, Barcelona, 08035, Spain|Hospital Infantil Universitario Nino Jesus, Madrid, 28009, Spain|Hospital Universitari i Politecnic La Fe de Valencia, Valencia, 46026, Spain|Alderhey Childrens Trust, Liverpool, L12 2AP, United Kingdom|Great Ormond Street Hospital; Dept. Of Pediatric Oncology, London, WC1N 3JH, United Kingdom|The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit, Newcastle Upon Tyne, NE1 4LP, United Kingdom Less <<
NCT02649972 Histiocytic Disorders PHASE2 COMPLETED 2022-12-16 Mayo Clinic, Rochester, Minnes... More >>ota, 55905, United States|Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States Less <<
NCT04409639 Chronic Myelomonocytic Leukemi... More >>a (CMML) Less << PHASE2 RECRUITING 2026-08-15 Oregon Health and Science Univ... More >>ersity, Portland, Oregon, 97239, United States|Huntsman Cancer Institute at University of Utah, Salt Lake City, Utah, 84112, United States|Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, United States Less <<
NCT01249131 Healthy Volunteers PHASE1 COMPLETED 2011-01-10 -

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.88mL

0.38mL

0.19mL

9.41mL

1.88mL

0.94mL

18.82mL

3.76mL

1.88mL

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