ABSTRACT
We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.
Subject(s)
Antineoplastic Agents , cdc42 GTP-Binding Protein , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Humans , Mice , cdc42 GTP-Binding Protein/antagonists & inhibitors , cdc42 GTP-Binding Protein/metabolism , Cell Line, Tumor , Drug Discovery , Structure-Activity Relationship , Xenograft Model Antitumor Assays , Pyrimidines/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , FemaleABSTRACT
Analysis of Phrynosoma blainvillii Gray from Marina, Monterey County, California, using 150 bp paired-end Illumina sequences (Illumina, San Diego, CA) resulted in the assembly of its complete mitogenome. The mitogenome is 16,946 bp in length and contains a putative origin of light strand replication (OL), control region, 22 tRNA, 2 rRNA, and 13 protein-coding genes. Its content and organization are similar to other Squamata. Phylogenetic analysis of P. blainvillii resolves it in a clade with P. sherbrookei Nieto-Montes de Oca, Arenas-Moreno, Beltrán-Sánchez & Leaché, sister in position to Uma notata Baird. Mitochondrial marker analysis of P. blainvillii from Marina shows that it belongs to a coastal Santa Lucia Mountain Range haplogroup that is distinct from other populations of P. blainvillii in California.
