BRAF Inhibitors in Melanoma Management: When Friends Become Foes

Abstract Background V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Results Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. Conclusion The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

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Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair

Oncogene ◽

10.1038/s41388-021-01879-2 ◽

2021 ◽

Author(s):

Josune Alonso-Marañón ◽

Alberto Villanueva ◽

Josep Maria Piulats ◽

María Martínez-Iniesta ◽

Laura Solé ◽

...

Keyword(s):

Dna Repair ◽

Malignant Melanoma ◽

Braf Inhibitors

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Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review

Journal of Cutaneous Medicine and Surgery ◽

10.1177/12034754211004560 ◽

2021 ◽

pp. 120347542110045

Author(s):

Sara Mirali ◽

Abrahim Abduelmula ◽

Asfandyar Mufti ◽

Muskaan Sachdeva ◽

Jensen Yeung

Keyword(s):

Systematic Review ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Complete Resolution ◽

Kinase Inhibitors ◽

Healthcare Providers ◽

Latency Period ◽

Braf Inhibitors ◽

Palmoplantar Keratoderma ◽

Drug Induced

Background Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK. Methods EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword “palmoplantar keratoderma.” 40 studies met the inclusion criteria. Results A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( n = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, n = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, n = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, n = 8/247), or chemotherapy (2.4%, n = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( n = 12/24) achieving complete resolution and 50% ( n = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( n = 10) and topical corticosteroids ( n = 4). Conclusions PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.

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EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

Neuro-Oncology ◽

10.1093/neuonc/noaa215.370 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii90-ii90

Author(s):

Nikita Dhir ◽

Sheila Chandrahas ◽

Chibuzo O’Suoji ◽

Mohamad Al-Rahawan

Keyword(s):

Targeted Therapy ◽

Brain Tumors ◽

Tumor Regression ◽

Case Series ◽

Pediatric Brain Tumors ◽

Braf V600e ◽

Cns Tumors ◽

Braf Inhibitors ◽

Pediatric Brain ◽

Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

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