plx4032 and Melanoma

Over the last few years, BRAF has emerged as a validated target in melanoma. This review summarises recent advances in the development of BRAF inhibitors, focussing on agents that have been assessed clinically.

Topics: Clinical Trials as Topic; Humans; Melanoma; Molecular Weight; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

Topics: Alleles; Animals; Dogs; Extracellular Signal-Regulated MAP Kinases; Humans; Indoles; Macaca fascicularis; MAP Kinase Signaling System; Melanoma; Models, Molecular; Mutant Proteins; Mutation; Neoplasm Metastasis; Phosphorylation; Positron-Emission Tomography; Proto-Oncogene Proteins B-raf; Rats; Substrate Specificity; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-

Topics: Animals; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Drug Stability; Half-Life; Humans; Imidazoles; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Docking Simulation; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Sulfonamides; Thiazoles; Transplantation, Heterologous

Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound 6f significantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Apoptosis; Autophagy; Carrier Proteins; Cell Line, Tumor; Cell Nucleus; Drug Screening Assays, Antitumor; Enzyme Activators; Humans; Indoles; Melanoma; Membrane Proteins; Models, Molecular; Neoplasms; Structure-Activity Relationship; Thiocarbamates; Thyroid Hormone-Binding Proteins; Thyroid Hormones

Metastatic melanoma is amongst the most difficult types of cancer to treat, with current therapies mainly relying on the inhibition of the BRAF

Topics: Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Light; Melanoma; Molecular Structure; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship

A series of novel thio- and seleno-barbituric acid derivatives were synthesized by varying the substituents at N1 and N3 (ethyl, methyl, allyl, and phenyl), and C5 tethered with dienyl and trienyl moieties attached to substituents such as phenyl, 2-furanyl, 2-thiophenyl, 1-naphthyl, and 3-pyridyl. The cytotoxic potential of these derivatives was evaluated by using MTT assay against melanoma cell lines expressing either wild-type (CHL-1) or mutant (UACC 903) BRAF gene. Among all, 2b and 8b were identified as the most potent compounds. Both 2b and 8b inhibited viability of various melanoma cells and induced cell death as evidenced by Live and Dead assay. Western blot analysis showed that they induce PARP cleavage and inhibit anti-apoptotic Bcl-2, Bcl-xL and Survivin in a dose-dependent manner within 24 h of the treatment. Novel thiobarbituric acid analogs also inhibited viability of various other solid tumor cell lines, such as pancreatic, breast, and colon. Overall, 2b, 2d, and 8b emerged as the most effective compounds and make good leads for the development of future therapeutic agents.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Melanoma; Molecular Structure; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thiobarbiturates; Tumor Cells, Cultured

Simutaneous targeting all Raf isoforms offers the prospect of enhanced efficacy as well as reduced potential for resistance. Described herein is the discovery and characterization of a series of pyrimidine scaffold with DFG-out conformation as potent Pan-Raf inhibitors. Among them, I-41 with excellent Pan-Raf potency demonstrates inhibitory activity against BRaf

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Humans; Melanoma; Protein Kinase Inhibitors; Pyrimidines; raf Kinases; Rats

Synthesis and anti-melanoma activity of novel naphthalimide isoselenocyanate (NISC) and naphthalimide selenourea (NSU) analogs are described. The novel agents were screened for growth inhibition of different human melanoma cell lines including those having BRAF

Topics: Antigens, Neoplasm; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Melanoma; Molecular Structure; Naphthalenes; Nitriles; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship

Melanoma is an aggressive form of skin cancer and it is generally associated with poor prognosis in patients with late-stage disease. Due to the increasing occurrence of melanoma, there is a need for the development of novel therapies. A new series of diarylamide and diarylurea derivatives containing imidazo[1,2-a]pyridine or imidazo[1,2-a]pyrazine scaffold was designed and synthesized to investigate their in vitro efficacy against the A375P human melanoma cell line. We found several compounds expressing submicromolar IC50 values against the A375P cells, from which 15d, 17e, 18c, 18h, 18i demonstrated the highest potencies with IC50 below 0.06 μM.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Imidazoles; Melanoma; Molecular Structure; Pyrazines; Pyridines; Structure-Activity Relationship

Cancer is the second cause of deaths worldwide and is forecasted to affect more that 22 million people in 2020. Despite dramatic improvement in its care over the last two decades, the treatment of resistant forms of cancer is still an unmet challenge. Thus, innovative and efficient treatments are still needed. In this context, we report herein the synthesis and the evaluation of a new class of bioactive molecules belonging to the N-(4-(3-aminophenyl(thiazol-2-yl)acetamide family. Structure-activity relationships could be driven and resulted in the discovery of lead compound 6b. The latter display high in vitro potency against both sensitive and resistant cancer cell lines on three models: melanoma, pancreatic cancer, and chronic myeloid leukemia (CML). 6b leads to cell death by concomitant induction of apoptosis and autophagy, shows good pharmacokinetic properties, and demonstrates a significant reduction of tumor growth in vivo on A375 xenograft model in mice.

Topics: Acetamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Melanoma; Mice; Pancreatic Neoplasms; Structure-Activity Relationship; Thiazoles

Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; ErbB Receptors; Genes, erbB-1; Humans; Indicators and Reagents; Indoles; Melanoma; Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Sulfonamides; Vemurafenib

Synthesis of a new series of diarylureas and diarylamides possessing 4-aryl-8-amino(acetamido)quinoline scaffold is described. Their in vitro antiproliferative activities against ten melanoma cell lines were tested. Compounds 1l, 2l, 3c, and 4c showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. Compound 4c was equipotent to Vemurafenib against A375P. In addition, compounds 1l, 2a, and 2l showed high potency over the NCI-9 tested melanoma cell line panel. The IC50 values of compounds 1l and 2l were in 2-digit nanomolar scale over four and five cell lines, respectively. Compound 2l showed high, dose-dependent inhibition of ERK kinase. ADME profiling showed that compounds 1l, 2l, 3c, 4c, and 5b are estimated to be orally bioavailable.

Topics: Acetamides; Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Computer Simulation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Extracellular Signal-Regulated MAP Kinases; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; Protein Kinase Inhibitors; Quinolines; Structure-Activity Relationship; Urea

The B-ring of Benzoazepinoisoquinolones 1a-b was successfully constructed by Pomeranz-Fritsch reaction. The key intermediates 5a-b could be transformed from 9a-b via Overman rearrangement. The bioassay showed that 11 compounds are more active than sorafenib (IC₅₀ = 7.56 μM) against A375 melanoma cell line, among which 1a, 5a, 8a and 10c with IC₅₀ values of 0.59, 0.20, 0.17 and 0.11 μM, respectively, showed potent cytotoxicity close to or even stronger than the anti-melanoma drug vemurafenib (IC₅₀ = 0.18 μM). In addition, 5a, 8a and 10c are more active than both vemurafenib and sorafenib on HCT116 colon cell line (IC₅₀ values: 0.86, 0.65, 0.42, >30 and 5.65 μM for 5a, 8a, 10c, vemurafenib and sorafenib). Therefore, these compounds are promising candidates for further drug development.

Topics: Antineoplastic Agents; Benzazepines; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HCT116 Cells; Hep G2 Cells; Humans; Indoles; K562 Cells; Melanoma; Molecular Structure; Niacinamide; Phenylurea Compounds; Quinolones; Sorafenib; Structure-Activity Relationship; Sulfonamides; Vemurafenib

A series of new diarylurea and diarylamide derivatives possessing acet(benz)amidophenyl scaffold was synthesized. Their in vitro antiproliferative activity was tested against A375P human melanoma cell line. Compounds 1c,d and 2c,d showed the highest potencies with IC(50) values in sub-micromolar scale. In addition, compounds 1b,e,l and 2e,l were more potent than Sorafenib but with IC(50) values in micromolar range. Moreover, compound 2c was equipotent to Vemurafenib, and 2d showed higher potency than Vemurafenib against A375P. Molar refractometry calculation and ADME profiling of the highest potent four derivatives 1c,d and 2c,d are also reported.

Topics: Amides; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Melanoma; Urea

A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino derivatives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds 8a and 9b-f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3 fibroblasts. Furthermore, compounds 8d, e and 9a-d, f demonstrated very high potencies against the nine tested melanoma cell lines at the NCI. The bisamide derivatives 9a-c, f showed 2-digit nanomolar IC(50) values over different cell lines of the NCI-9 melanoma cell lines.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Melanoma; Pyridines; Pyrroles; Structure-Activity Relationship