Development of Benzimidazole Compounds for Cancer Therapy

A fact that is largely unknown in the lay press and even the scientific community is that today cancer kills more people worldwide than tuberculosis (TB), malaria, and human immunodeficiency virus (HIV) combined. Benzimidazole is a heterocyclic aromatic organic compound considered to be a useful pharmacophore in a variety of impactful drugs. The purpose of this review is to highlight the benzimidazole-containing agents that are currently in clinical use or in clinical development as anticancer drugs. It is hoped that this review would function as comprehensive working reference of research accomplishment in the field of discovery and development of benzimidazole-based anticancer drugs

Ability of plant callus cultures to synthesize and accumulate lower terpenoids

Callus cultures derived from seven oil-producing plants have been maintained under different regimes of media, temperature and illumination, and have been assayed for ability both to synthesize and to accumulate mono- and sesqui-terpenes. Callus of Pinus radiata (the sole gymnosperm) accumulated (α- and β-pinenes at levels comparable with those in the parent stem and needles; and that of Jasminum officinale accumulated traces of several monoterpenes (< 0.1 % the amount in petals) but cultures of Rosmarinus officinalis, Lavandula angustifolia, Anethum graveolens, Ocimum basilicum and Tanacetum vulgare did not detectably accumulate the lower terpenoids or secrete them into the medium. However, all seven culture lines yielded cell-free extracts containing prenyltransferase and an isomerizing system (as assayed by conversion of IPP into GPP, NPP and FPP) with activities some fold greater than those extracted from the parent mature plants, or up to 90-fold the levels extractable from young seedlings of the various species. Callus of five of the species (A. graveolens and O. basilicum were not assayed) also contained MVA-kinase, MVAP-kinase, MVAPP-decarboxylase and IPP-DMAPP isomerase at levels comparable with those in the parent tissue. Hence the angiosperms yielded cultures that presumably contained the crucial enzyniic machinery necessary for the synthesis of the lower terpenoids, although accumulation of those compounds did not occur. Reasons for this unexpected situation are discussed. These results imply that callus cultures may be a convenient source of biomass for studies on the enzymes of terpenoid biosynthesis

Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors

A series of novel 1H- and 2H-indazole derivatives of the commercially available dehydroepiandrosterone acetate have been synthesized and tested for inhibition of human cytochrome 17[alpha]-hydroxylase-C17,20-lyase (CYP17), androgen receptor (AR) binding affinity, and cytotoxic potential against three prostate cancer (PC) cell lines.http://www.sciencedirect.com/science/article/B6TC9-4PF1WHS-2/1/094a9de6c64caef045c1b0cf212e563

Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo

Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98–0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders

Regulation of Androgen Receptor Activity by Tyrosine Phosphorylation

The androgen receptor (AR) is essential for the growth of prostate cancer cells. Here, we report that tyrosine phosphorylation of AR is induced by growth factors and elevated in hormone-refractory prostate tumors. Mutation of the major tyrosine phosphorylation site in AR significantly inhibits the growth of prostate cancer cells under androgen-depleted conditions. The Src tyrosine kinase appears to be responsible for phosphorylating AR, and there is a positive correlation of AR tyrosine phosphorylation with Src tyrosine kinase activity in human prostate tumors. Our data collectively suggest that growth factors and their downstream tyrosine kinases, which are elevated during hormone-ablation therapy, can induce tyrosine phosphorylation of AR and such modification may be important for prostate tumor growth under androgen-depleted conditions

Regulation of Androgen Receptor Activity by Tyrosine Phosphorylation

The androgen receptor (AR) is essential for the growth of prostate cancer cells. Here, we report that tyrosine phosphorylation of AR is induced by growth factors and elevated in hormone-refractory prostate tumors. Mutation of the major tyrosine phosphorylation site in AR significantly inhibits the growth of prostate cancer cells under androgen-depleted conditions. The Src tyrosine kinase appears to be responsible for phosphorylating AR, and there is a positive correlation of AR tyrosine phosphorylation with Src tyrosine kinase activity in human prostate tumors. Our data collectively suggest that growth factors and their downstream tyrosine kinases, which are elevated during hormone-ablation therapy, can induce tyrosine phosphorylation of AR and such modification may be important for prostate tumor growth under androgen-depleted conditions