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The ability to control the proliferation and cell death by inhibiting specific target kinase offers the opportunity to apply targeted therapies in the treatment of cancer. It has been found that (S)-valine-thiazole-derived compounds such as NEOS-223 are effective inhibitors of one or more of these kinases. NEOS 223 was developed, synthesized, and tested in the NCI 60 human tumor cell-screening panel demonstrating inhibition of colon (-53%), melanoma (-41%), and breast cancers (-9%). Microsomal clearance was determined in mouse, rat, dog, and human, and analyzed by LC-MS/MS by percent of parent material. IC50 values for CYP inhibition of >10 μM were calculated for 1A2, 2C19, and 3A4 with IC50 values of 4.86, 4.31, and 7.84 μM for 2C9 and 2D6. Microsomal clearance was high in all species with clearance rates ranging from 69-136 mL/min/kg. Plasma protein binding was determined by Rapid Equilibrium Dialysis in mice, rats, dogs, and humans. High plasma protein binding (>70%) was observed across all species. Based on the NCI results several cell lines were assayed in an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide) to determine cell viability in the presence of NEOS-223 resulting in in vivo efficacy resulted in inhibition of growth of multiple cell line. As a novel effective structure possibly targeting multiple kinases and transporters in one hybrid molecule, NEOS-223 may be a preferred monotherapy or combined therapy for multiple cancers. If upon further development, this drug is effective in humans, it would advance clinical practice and could improve current therapy significantly. Citation Format: Sumathi Chittamuru, Timothy M. Murphy, Sara A. Little, Andrew A. Taylor, Roseanne Wexler, Laxman Desai. Pre-clinical evaluation of NEOS-223, an (S)-valine-thiazole derived peptidomimetic N-heterocycle, as an anticancer agent and P-glycoprotein inhibitor [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P39.

e14509Background: Cyclin dependent kinases (CDK) play a vital role in cell cycling and proliferation. Altered expression of these kinases in malignant cells results in deregulation of cell cycle ac...

1. 1. The glycine-arginine-rich histones isolated from bovine lymphosarcoma and Novikoff hepatoma have been found to have virtually the same amino acid compositions as that of fetal cal thymus and calf thymus published previously 8,9 . 2. 2. The glycine-arginine-rich histones isolated from fetal calf thymus, bovine lymphosarcoma and Novikoff hepatoma were cleaved with cyanogen bromide to yield two peptides. The C-terminal CN-2 peptide for each histone was isolated by the use of Sephadex G-100. The C-terminal CN-2 peptide for each of these three tissues was found to have the same amino acid composition as that from calf thymus 12 . 3. 3. The C-terminal peptides, CN-2, of bovine lymphosarcoma, fetal calf thymus and Novikoff hepatoma were hydrolyzed with trypsin. In each case five peptides were obtained by peptide mapping and ion-exchange chromatography. The amino acid compositions of these peptides were identical for each of the tissues and to that found for calf thymus previously. 4. 4. It was concluded that the C-terminal portion of the glycine-arginine-rich histones isolaetd from these four tissues are identical with each other and with that of pea seedling 11 .