Hit-to-lead and lead optimization of kinase modulators

We use the tools of synthetic organic chemistry, medicinal chemistry, and chemical biology to develop small molecules for studying and modulating therapeutically relevant cancer targets. Current work in the laboratory focuses on the development of IND safety assessment candidates that inhibit the transcriptional kinases CDK12 and CDK13, the Wnt/beta-catenin regulators CK1δ and CK1ε, and the autophagy kinase ULK1. 

For CDK12/13 project, we identified N9 heteroaromatic purines with high nanomolar affinity against CDK12 and CDK13 via unrelated HTS screening campaign from Scripps library of kinase inhibitors. The initial hit compound had poor CDK12 selectivity and inferior pharmacokinetic properties. Basic in vitro ADME properties such as solubility, permeability, logD, metabolic stability, and CYP inhibition are routinely tested in the Monastyrskyi laboratory. SAR and DMPK data are carefully taken into consideration in the iterative process of inhibitor design and optimization (see Research Operation Plan). Additional rounds of SAR guided by structure-based drug design were performed around purine scaffold that resulted in the identification of current lead purine compound – a potent, selective, non-covalent and orally bioavailable inhibitor of CDK12/13.


Research Operating Plan (ROP) with key parameters and target values for safety assessment candidate selection (SAC) and IND enabling studies. Each box represents an assay(s), the progression path is indicated by arrows

Kinetic target-guided synthesis

Kinetic Target-Guided Synthesis (TGS) strategy is a powerful yet unconventional approach in which the biological target is actively engaged in the design and the synthesis of its own inhibitory compounds in the irreversible fashion. Fragments bind to the biological target – a protein on DNA/RNA fragment sites – simultaneously with reacting groups positioned within conformational reach of each other, increasing their effective molarity. Although kinetic TGS was conceptually proposed in the 1980s, it is still relatively unexplored in comparison to other fragment-based approaches.

The Monastyrskyi laboratory is interested in the development of kinetic TGS approaches and application thereof for the discovery and optimization of small molecules RNA and RNA-protein interaction modulators. RNA dynamic flexibility is a challenging property to overcome in the rational drug design, however, it also represents an opportunity for probing a structurally diverse set of ligands with a goal of developing higher affinity inhibitors in situ. Our ideas are aimed at developing synthesis and screening methods that generate biologically active compounds for the variety of otherwise “undruggable” cancer targets such as transcription factors c-Myc, TWIST1, SNAIL1, etc.


Target-templated fragment ligation in kinetic TGS