Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

Keating, Gillian M.

doi:10.1007/s40265-016-0562-7

Cited by 18 publications

(6 citation statements)

References 55 publications

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“…As previously discussed with 26, some of these adverse events and resistance-associated mechanisms have lower incidence in patients receiving the combination than those on monotherapy with 16. 256 The synthesis is a convergent pathway that requires the prior preparation of intermediates XXXIa and XXXIb (Scheme 31). 257−259 Intermediate XXXIa is synthesized by converting 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid into the corresponding acid fluoride.…”

Section: Fda-approved Kinase Inhibitors From 1999 To 2010mentioning

confidence: 99%

“…Discovered by Exelixis (GDC-0973, XL518), 31 was developed in collaboration with Genentech (Roche group) and is marketed under the trade name of Cotellic. The coBRIM phase 3 trial, , comparing 31 plus the BRAF inhibitor 16 with placebo plus 16 , supported the approval of the combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF-V600E or BRAF-V600K mutation by the FDA and the Swiss Agency for Therapeutic Products (Swissmedic) in 2015.…”

Section: Fda-approved Kinase Inhibitors From 2011 To 2015mentioning

confidence: 99%

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Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

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The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

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Section: Fda-approved Kinase Inhibitors From 1999 To 2010mentioning

confidence: 99%

Section: Fda-approved Kinase Inhibitors From 2011 To 2015mentioning

confidence: 99%

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

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“…122 Combination of cobimetinib with vemurafenib, an important BRAF inhibitor, 123 enables targeting of multiple points on the MAPK pathway, leading to overall enhanced tumor cell apoptosis and response as compared to stand-alone treatment with vemurafenib. 124 Specifically, in a representative trial of previously untreated patients with BRAF V600 mutation-positive, unresectable, stage IIIc or IV melanoma, combination of these two therapies led to a significantly improved progression-free survival and overall response rate versus patients treated only with vemurafenib. 124a, 125 Structurally, cobimetinib features an interesting azetidinol substructure appended to the 2-position of a piperidine, rendering the 2-carbon of the piperidine as a stereogenic center bearing the (S)-configuration.…”

Section: Metabolic Drugsmentioning

confidence: 99%

Synthetic Approaches to the New Drugs Approved During 2015

et al. 2017

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New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.

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“…To overcome the drug acquired resistance of melanoma, combination treatments of BRAFi with MEKi had become the default therapies for patients with advanced BRAF V600 -mutated melanoma. Vem/cobimetinib treatment was reported to inhibit cell proliferation in melanoma cells ( 64 , 65 ), and abrogate the paradoxical activation of the MAPK pathway and inhibit glucose metabolism pathway ( 66 ), but no inhibition of other pathways was reported. In this study, DMF/Vem treatment suppressed the phosphorylation of ERK1, AKT and 4EBP1 more effectively than either DMF or Vem treatment did ( Figures 6A–F ), indicating DMF/Vem treatment simultaneously inhibited the activation of MAPK and AKT/mTOR signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells

Wang

Jia

et al. 2022

Front. Oncol.

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Melanoma is a deadly form of skin cancer with high rates of resistance to traditional chemotherapy and radiotherapy. BRAF inhibitors (BRAFi) can achieve initial efficacy when used to treat melanoma patients, but drug resistance and relapse are common, emphasizing the need for new therapeutic strategies. Herein, we reported that combination of dimethyl fumarate (DMF) and vemurafenib (Vem) inhibited melanoma cell proliferation more significantly and induced more cell death than single agent did both in vitro and in vivo. DMF/Vem treatment induced cell death through inhibiting the expression and transcriptional activity of NRF2 thereby resulting in more reactive oxygen species (ROS) and via inhibiting the expression of YAP, a key downstream effector of Hippo pathway. DMF/Vem treatment also reduced phosphorylation of AKT, 4EBP1, P70S6K and ERK in AKT/mTOR/ERK signaling pathways. RNA-seq analysis revealed that DMF/Vem treatment specifically suppressed 4561 genes which belong to dozens of cell signaling pathways. These results indicated that DMF/Vem treatment manifested an enhanced antitumor efficacy through inhibiting multiple cell signaling pathways, and thus would be a novel promising therapeutic approach targeted for melanoma.

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Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

Cited by 18 publications

References 55 publications

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Synthetic Approaches to the New Drugs Approved During 2015

Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells

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