PHA-767491 HCl

PHA-767491 HCl (CAS No.: 942425-68-5) is a synthetic small-molecule, ATP-competitive dual-target kinase inhibitor that specifically acts on the Cdc7–Dbf4 complex (DDK) and cyclin-dependent kinase 9 (CDK9). It serves as a laboratory research tool for dissecting DNA replication control and transcriptional regulation, belongs to the category of cell cycle and kinase pathway probes, and is mainly applied in studies of DNA replication initiation, MCM helicase activation, and RNA polymerase II-dependent transcription elongation. Mechanistically, by inhibiting DDK, it blocks phosphorylation-dependent activation of the MCM complex and replication origin firing, induces replication stress, and leads to S-phase arrest; meanwhile, inhibition of CDK9 can reduce phosphorylation of the Ser2 site in the C-terminal domain of RNA polymerase II, thereby modulating transcription elongation and related gene expression programs. Biochemical assays show that it has nanomolar potency against DDK and CDK9, with IC50 values of approximately 10 nM and 34 nM, respectively, and exhibits about 20-fold selectivity over GSK3-β and CDK1/2, about 50-fold selectivity over CDK5 and MK2, and about 100-fold selectivity over CHK2 and PLK1, supporting mechanistic studies that require a certain degree of target discrimination. In cellular experiments, its activity is typically in the nanomolar to low micromolar range, can inhibit DNA synthesis markers, and can trigger readout signals related to programmed cell death in some tumor-derived cell lines, consistent with on-target intervention in the replication and transcription axis. Typical applications include target validation, signaling pathway dissection, and dependency screening. It can be used as a single-agent treatment or combined with other perturbing factors to map synthetic vulnerability profiles, and may be used in ethically approved animal models for pharmacodynamic or biomarker dynamic observations. The concentration or dose used in experiments usually depends on the specific experimental design and research objectives. This material is for laboratory research use only and is strictly prohibited for human or veterinary-related applications.