Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

Abstract

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.

Overcoming resistance to BRAF inhibitors

“…The rationale of these approaches is to prevent or overcome MAPK inhibitor dependent resistance mechanisms, although the appearance of systemic toxicities remains one of the main concerns when combining several small molecules (115)(116)(117)(118)(119). Other groups have attempted to tackle mechanisms of resistance related to the appearance of mutations in MEK1/2 and novel MEK inhibitors active in some of these mutants show interesting potential (120).…”

Discriminatory analysis based molecular docking study for in silico identification of epigallocatechin-3-gallate (EGCG) derivatives as B-RafV600E inhibitors

“…7 Furthermore, this mutation type causes B-Raf to signal independently from upstream regulation. 4 In an effort to selectively target the B-Raf V600E mutant, numerous clinically used small molecule inhibitors have been published, including…”

One‐Pot Synthesis of N‐Aryl‐Nicotinamides and Diarylamines Based on a Tunable Smiles Rearrangement

“…For example, they serve as succinate dehydrogenase inhibitors that belong to a significant category of fungicides and pesticides in agrochemical application 8. Considering the broad interest of this heterocyclic building block, three general synthetic methods were taken into consideration (Figure 2): 1) amidation of nicotinic acid/nicotinyl chloride with aniline;7e,9 2) transamidation of primary nicotinamides with amines;10 and 3) transition metal‐catalyzed coupling reactions between aryl halides/pseudohalides and nicotinamide 11. However, from a practical perspective, environmentally benign, atom‐economical, and metal‐free conditions, are still needed to fulfil the high demand for synthesizing this N ‐aryl‐nicotinamide scaffold.…”