A novel anti-melanoma SRC-family kinase inhibitor

Abstract

The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth in vivo . As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.

Integrative Molecular and Clinical Profiling of Acral Melanoma Identifies LZTR1 as a Key Tumor Promoter and Therapeutic Target

“…5h, i). These results are consistent with our published observations using the same melanoma cell lines 69 .…”

“…We used western blots to identify the levels of proteins as previously described 69 . Cell extracts (20 µg/lane) were fractionated in 3%-8% or 4-12 % tris-acetate gel (NP0006, NuPAGE Life Technologies).…”

Novel Pyrazolo[3,4‐d]pyrimidine‐Containing Amide Derivatives: Synthesis, Molecular Docking, In Vitro and In Vivo Antidiabetic Activity

“…Pyrazolo[3,4‐ d ]pyrimidines are reported to have various pharmacological activities viz., antiviral, anticoccidials, antimicrobial antitumor, herbicidal, antileukemic, CNS agents, tuberculostatic, antileishmanial, anti‐inflammatory and cardiovascular activities. They are also mainly found to show variable degrees of anticancer activities against HCC, cervical carcinoma, colon carcinoma, skin carcinoma, and breast adenocarcinoma, by inhibiting different types of enzymes such as EGFR‐TK, CDK, B‐Raf kinase, Src and Abl tyrosine kinase, and glycogen synthase kinase‐3 …”

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-src Tyrosine Kinase

“…Furthermore, c-src tyrosin kinase has been shown to be abnormally activated or overexpressed in a number of different malignancies and to stimulate processes associated with tumor progression, such as proliferation, angiogenesis, or metastasis [10]. Src tyrosin kinase inhibitors have been explored as potential new therapeutic agents in a variety of malignancies such as melanoma (one such inhibitor demonstrating in vitro activity on a variety of melanoma cells, including some BRAF V600 mutant cells [11], but a report that src inhibition would induce melanogenesis in melanoma cells has also been published [12]), papillary thyroid carcinoma [13], clear-cell renal carcinoma [14], pancreatic [15], or ovarian cancer [16].…”