Design and Synthesis of Novel 3-Pyrimidyl Pyrrolo [2,3-B] Pyridine As Cyclin-Dependent-Kinase Inhibitors With Potent In-Vitro, Along With Better Pharmacokinetics and In-Vivo Antitumor Efficacy

Cyclin-dependent kinases (CDKs) has attracted major interest, as they regulate the cell-division, apoptosis, transcription, and differentiation, and are found deregulated in the number of malignancies viz., cancer, neurodegenerative disorders, inflammation, infectious diseases. In this direction, meriolins (3-pyrimidyl pyrrolo [2,3-b]pyridine derivatives), is known for inhibiting both cell-cycle and transcriptional CDKs, CDK2, and CDK9, respectively, representing an important lead structure for further exploration. Despite nanomolar potency in-vitro and good in-vivo efficacy of meriolin, they have poor PK/PD properties and limits further development. Therefore, we have started the medicinal chemistry of 3-pyrimidyl pyrrolo [2,3-b]pyridine skeleton to discover new generation analogs having potency against both cell-cycle and transcriptional CDKs along with better PK/PD behavior.1,2 In the present study, a series of novel analogs of 3-pyrimidyl pyrrolo [2,3-b]pyridine skeleton was designed using bioinformatics strategy and synthesized by Masuda-borylation-Suzuki-coupling reaction (MBSC). As per our strategy, all the synthesized compounds were initially screened against CDK2/cyclinA and CDK9/cyclinT targets in the cell-free assay and most of them shown nano-molar potency, which then taken up for cell-based screening against different cancerous cell line. The compounds having potent activity in both cell-free and cell-based assays were selected for solubility study followed by pharmacokinetic exposure, interestingly these compounds showed improved in-vivo PK profile. Further, the identified lead has also shown in vivo efficacy in a mouse solid tumor model with TGI (tumor growth inhibition) of ~ 60 % without any mortality in comparison to reported leads.