Cobimetinib
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MedKoo CAT#: 203185

CAS#: 934660-93-2 (free base)

Description: Cobimetinib, also known as GDC-0973 and XL-518, RG 7420, is an orally bioavailable small-molecule inhibitor of mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. MEK inhibitor GDC-0973 specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types.


Chemical Structure

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Cobimetinib
CAS# 934660-93-2 (free base)

Theoretical Analysis

MedKoo Cat#: 203185
Name: Cobimetinib
CAS#: 934660-93-2 (free base)
Chemical Formula: C22H22F3IN2O2
Exact Mass: 530.06781
Molecular Weight: 530.32196
Elemental Analysis: C, 49.83; H, 4.18; F, 10.75; I, 23.93; N, 5.28; O, 6.03

Price and Availability

Size Price Availability Quantity
25.0mg USD 250.0 2 Weeks
50.0mg USD 450.0 2 Weeks
100.0mg USD 750.0 2 Weeks
200.0mg USD 1250.0 2 Weeks
500.0mg USD 1950.0 2 Weeks
1.0g USD 2950.0 2 Weeks
2.0g USD 4950.0 2 Weeks
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Related CAS #: 1369665-02-0 (hemifumarate)   934660-93-2 (free base)    

Synonym: XL518; XL 518; XL-518; GDC0973; GDC 0973; GDC-0973; RG 7420; RG-7420; RG7420; cobimetinib; Cotellic.

IUPAC/Chemical Name: (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)cyclobutyl)methanone.

InChi Key: FIAWSLMDMMCNMU-HHCSFTFJSA-N

InChi Code: InChI=1S/C22H22F3IN2O2/c23-15-6-5-14(20(19(15)25)28-17-7-4-13(26)9-16(17)24)21(29)12-10-22(30,11-12)18-3-1-2-8-27-18/h4-7,9,12,18,27-28,30H,1-3,8,10-11H2/t12?,18-,22?/m0/s1

SMILES Code: O=C(C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F)C3CC([C@H]4NCCCC4)(O)C3

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: Cobimetinib (GDC-0973, RG7420) is a potent, selective and oral MEK1 inhibitor with an IC50 of 4.2 nM for MEK1.
In vitro activity: Neuroblastoma cell lines IMR-32, SHEP and IMR-5 were incubated in the absence or presence of cobimetinib (1 μM) for 24 hour and cell lysates were analyzed by western blot. IMR-32 and SHEP showed PARP cleavage as indication of apoptosis induction. To further confirm this finding an Annexin V/PI binding assay was performed (Fig. 6a and b). This data revealed an increased percentage of early apoptotic cells (Annexin V+/PI−) after treatment of IMR-32 and IMR-5 cells with cobimetinib for 24 h. Reference: J Exp Clin Cancer Res. 2015; 34(1): 104. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575431/
In vivo activity: In addition, this study validated the in vitro findings in HCC xenograft mouse model and demonstrated that cobimetinib inhibited ERK signaling, promoted apoptosis, and was active against resistant HCC growth and angiogenesis in vivo, without causing significant toxicity in mice. Reference: Biochem Biophys Res Commun. 2020 Feb 26;523(1):147-152. https://pubmed.ncbi.nlm.nih.gov/31836141/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 75.0 141.42
DMF 33.0 62.23
Ethanol 29.0 54.68

Preparing Stock Solutions

The following data is based on the product molecular weight 530.32196 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Tong X, Wang Q, Wu D, Bao L, Yin T, Chen H. MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 2020 Feb 26;523(1):147-152. doi: 10.1016/j.bbrc.2019.12.032. Epub 2019 Dec 11. PMID: 31836141. 2. Singh A, Ruan Y, Tippett T, Narendran A. Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34(1):104. doi: 10.1186/s13046-015-0222-x. PMID: 26384788; PMCID: PMC4575431.
In vitro protocol: 1. Tong X, Wang Q, Wu D, Bao L, Yin T, Chen H. MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 2020 Feb 26;523(1):147-152. doi: 10.1016/j.bbrc.2019.12.032. Epub 2019 Dec 11. PMID: 31836141. 2. Singh A, Ruan Y, Tippett T, Narendran A. Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34(1):104. doi: 10.1186/s13046-015-0222-x. PMID: 26384788; PMCID: PMC4575431.
In vivo protocol: 1. Tong X, Wang Q, Wu D, Bao L, Yin T, Chen H. MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 2020 Feb 26;523(1):147-152. doi: 10.1016/j.bbrc.2019.12.032. Epub 2019 Dec 11. PMID: 31836141.

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1: Krens S, van der Meulen E, Jansman FGA, Burger DM, van Erp NP. Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC-MS/MS. Biomed Chromatogr. 2019 Nov 22:e4758. doi: 10.1002/bmc.4758. [Epub ahead of print] PubMed PMID: 31758580.

2: Asfuroglu M, Asfuroğlu Y. A novel side effect of mitogen-activated protein kinase inhibitor cobimetinib: Acute corneal decompensation. Indian J Ophthalmol. 2019 Dec;67(12):2073-2075. doi: 10.4103/ijo.IJO_2025_18. PubMed PMID: 31755464.

3: Poduje S, Marić Brozić J, Prkačin I, Delaš Aždajić M, Goren A. Vemurafenib and cobimetinib - induced toxic epidermal necrolysis in a patient with metastatic melanoma. Dermatol Ther. 2019 Nov 21. doi: 10.1111/dth.13174. [Epub ahead of print] PubMed PMID: 31750971.

4: Ribas A, Daud A, Pavlick AC, Gonzalez R, Lewis KD, Hamid O, Gajewski TF, Puzanov I, Wongchenko M, Rooney I, Hsu JJ, Yan Y, Park E, McArthur GA. Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma. Clin Cancer Res. 2019 Nov 15. doi: 10.1158/1078-0432.CCR-18-4180. [Epub ahead of print] PubMed PMID: 31732523.

5: Moyon Q, Boussouar S, Maksud P, Emile JF, Charlotte F, Aladjidi N, Prévot G, Donadieu J, Amoura Z, Grenier P, Haroche J, Aubart FC. Lung Involvement in Destombes-Rosai-Dorfman Disease: Clinical and Radiological Features and Response to the MEK Inhibitor Cobimetinib. Chest. 2019 Oct 24. pii: S0012-3692(19)34099-1. doi: 10.1016/j.chest.2019.09.036. [Epub ahead of print] PubMed PMID: 31669429.

6: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548657/ PubMed PMID: 31643968.

7: King AC, Diamond EL, Orozco JS, Morse HR, Ouyang LL, Schöder H, Rampal RK. Cobimetinib-induced "dropped head syndrome" and subsequent disease management in an Erdheim-Chester patient. Clin Case Rep. 2019 Sep 10;7(10):1989-1993. doi: 10.1002/ccr3.2297. eCollection 2019 Oct. PubMed PMID: 31624624; PubMed Central PMCID: PMC6787838.

8: Sorich MJ, Rowland A, Hopkins AM. Validation of dabrafenib-trametinib prognostic groups in patients treated with vemurafenib and cobimetinib for advanced BRAF-mutated melanoma. Melanoma Res. 2019 Aug 14. doi: 10.1097/CMR.0000000000000634. [Epub ahead of print] PubMed PMID: 31425480.

9: Lewis KD, Larkin J, Ribas A, Flaherty KT, McArthur GA, Ascierto PA, Dréno B, Yan Y, Wongchenko M, McKenna E, Zhu Q, Mun Y, Hauschild A. Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM. Br J Cancer. 2019 Oct;121(7):522-528. doi: 10.1038/s41416-019-0546-y. Epub 2019 Aug 16. PubMed PMID: 31417188.

10: Razanamahery J, Malakhia A, Guillon B, Humbert S, Magy-Bertrand N. Multiple arterial thrombosis and pericarditis revealing histiocytosis successfully treated with MEK-inhibitor cobimetinib. Clin Exp Rheumatol. 2019 Jul 22. [Epub ahead of print] PubMed PMID: 31376269.

11: Pfeifle I, Bohnekamp J, Volkhardt A, Kirsten H, Rohwedder A, Thum A, Magin TM, Kunz M. MEK inhibitor cobimetinib rescues a dRaf mutant lethal phenotype in Drosophila melanogaster. Exp Dermatol. 2019 Sep;28(9):1079-1082. doi: 10.1111/exd.14010. Epub 2019 Aug 19. PubMed PMID: 31338879.

12: Iafolla MA, Ramsay J, Wismer J, McWhirter E. Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report. SAGE Open Med Case Rep. 2019 May 16;7:2050313X19847358. doi: 10.1177/2050313X19847358. eCollection 2019. PubMed PMID: 31205706; PubMed Central PMCID: PMC6537058.

13: Lewis K, Hauschild A, Larkin J, Ribas A, Flaherty KT, McArthur GA, Dréno B, McKenna E, Zhu Q, Mun Y, Ascierto PA. Effect of concomitant dosing with acid-reducing agents and vemurafenib dose on survival in patients with BRAF(V600) mutation-positive metastatic melanoma treated with vemurafenib ± cobimetinib. Eur J Cancer. 2019 Jul;116:45-55. doi: 10.1016/j.ejca.2019.05.002. Epub 2019 Jun 4. PubMed PMID: 31173962.

14: Sullivan RJ, Hamid O, Gonzalez R, Infante JR, Patel MR, Hodi FS, Lewis KD, Tawbi HA, Hernandez G, Wongchenko MJ, Chang Y, Roberts L, Ballinger M, Yan Y, Cha E, Hwu P. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019 Jun;25(6):929-935. doi: 10.1038/s41591-019-0474-7. Epub 2019 Jun 6. PubMed PMID: 31171876.

15: Diamantopoulos PT, Lakiotaki E, Kyriakakis G, Gogas H. New primary melanoma in a patient under triple therapy with vemurafenib, cobimetinib, and atezolizumab for metastatic melanoma. Melanoma Res. 2019 May 30. doi: 10.1097/CMR.0000000000000627. [Epub ahead of print] PubMed PMID: 31157737.

16: Han L, Zhang Q, Dail M, Shi C, Cavazos A, Ruvolo VR, Zhao Y, Kim E, Rahmani M, Mak DH, Jin SS, Chen J, Phillips DC, Bottecelli Koller P, Jacamo R, Burks JK, DiNardo C, Daver N, Jabbour E, Wang J, Kantarjian HM, Andreeff M, Grant S, Leverson JD, Sampath D, Konopleva M. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models. Haematologica. 2019 May 23. pii: haematol.2018.205534. doi: 10.3324/haematol.2018.205534. [Epub ahead of print] PubMed PMID: 31123034.

17: Shapiro GI, LoRusso P, Kwak E, Pandya S, Rudin CM, Kurkjian C, Cleary JM, Pilat MJ, Jones S, de Crespigny A, Fredrickson J, Musib L, Yan Y, Wongchenko M, Hsieh HJ, Gates MR, Chan IT, Bendell J. Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors. Invest New Drugs. 2019 Apr 24. doi: 10.1007/s10637-019-00776-6. [Epub ahead of print] PubMed PMID: 31020608.

18: Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. doi: 10.1016/S1470-2045(19)30027-0. Epub 2019 Apr 16. Erratum in: Lancet Oncol. 2019 Jun;20(6):e293. PubMed PMID: 31003911.

19: Hellmann MD, Kim TW, Lee CB, Goh BC, Miller WH, Oh DY, Jamal R, Chee CE, Chow LQM, Gainor JF, Desai J, Solomon BJ, Das Thakur M, Pitcher B, Foster P, Hernandez G, Wongchenko MJ, Cha E, Bang YJ, Siu LL, Bendell J. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann Oncol. 2019 Jul 1;30(7):1134-1142. doi: 10.1093/annonc/mdz113. PubMed PMID: 30918950.

20: Engel S, Luessi F, Henning B, Bittner S, Loquai C, Zipp F. Vemurafenib and cobimetinib combination therapy for BRAFV600E-mutated melanoma favors posterior reversible encephalopathy syndrome. Ann Oncol. 2019 Mar 26. pii: mdz114. doi: 10.1093/annonc/mdz114. [Epub ahead of print] PubMed PMID: 30911762.



Additional Information

Cobimetinib was approved in 2015 To be used in combination with vemurafenib to treat advanced melanoma that has spread to other parts of the body or can’t be removed by surgery, and that has a certain type of abnormal gene (BRAF V600E or V600K mutation)