Synthesis, Biological Evaluation And 3D QSAR Studies Of Novel 4,5-dihydro-1H-pyrazole Derivatives As BRAF Inhibitors

Melanoma is a kind of uncommon and high level malignant cancer, with a high lethality rate of about 80%. It is one of the main contributor to cutaneous carcinoma lethality rate. Early treatment can be conducted by surgical excision, but the treatment of advanced melanoma can be very knotty and very few drugs can be used for it. By the recent, along with the fast development of the biology science and the computer science, targeted therapy for cancer is attracting more and more researchers’ attentions. And owing to the researching work continuously pouring into targeted therapy, this kind of technology become gradually mature and several targeted drugs are ready in clinical trial or into the market. Targeted therapy has also been reported in the treatment of advanced melanoma and several drugs with have been approved by FDA, e.g. sorafenib, dabrafenib, vemurafenib.MAPK RAS/RAF/MEK/ERK signaling path as one of the very base signaling paths in cells was found to have a very close relationship with uncontrolled proliferation of cancer cells. And researches show that BRAF is one the very kinases related to melanoma. BRAF is a protooncogene. It found 8% of cancers appear BRAF mutation of the V change into an E at site 600 (V600E). The mutation resulted in highly activated MAPK signaling transport and further promoting the cancer proliferation, survival and transfer. So, for these years, inhibitors targeting BRAFV600E kinase are developed with several sound effective ones, e.g. vemurafenib, dabrafenib.This paper focuses on the modification of compound SB-590885 of GSK. And a series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. Results of the bioassays against BRAFV600E and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC50 and GI50 value in low micromolar range, among which compound 27e (IC50= 0.20μM, GI50= 0.89μM) was bearing the best bioactivity comparable with the positive control Erlotinib.Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAFV600E inhibitory activity.