Targeting CDK9-Dependent Superenhancer Addiction in Idiopathic Pulmonary Fibrosis with Orally Available Small-Molecule Inhibitors
Abstract
Current treatment for pulmonary or idiopathic pulmonary fibrosis (IPF) regardless of subtype or stage is less than optimal, but increased evidence of disease pathophysiology and genomics has led to clinical investigation of novel targeted therapeutics and many rationale strategies. Cyclin-dependent kinase 9 (CDK9) is highly dysregulated in many lung fibrosis, particularly in tissue lung slice cells derived from IPF patients. In clinical IPF patients, CDK9, reported to facilitate progressive fibrosing interstitial pneumonia, promotes drug resistance to IPF agents. IPF patients who developed resistance to current therapy had elevated CDK9 expression. Elevated CDK9 expression is also reported to increase resistance to other agent in development in patient derived lung fibrotic cells. The loss or inhibition of CDK9 increased susceptibility to these targeted agents and more recently, inhibition of CDK9 was shown to stimulate immunity, raising the possibility of a potential synergy between CDK9 and super-enhancers (MCL-1, MYC and cyclic D1) inhibition. Together, these studies highlight the potential of CDK9 inhibitors alone to achieve immunity for treatment of chronic IPF disease. We established the fragment-based design strategies to improve the selectivity of newly designed CDK9 inhibitors utilizing in silico strategies coupled with the crystal structure of CDK. Utilizing the CDK9 refined model, we then implemented the ICM Ligand Editor on fly and cross-docking methodologies. We performed a series of docking and MD experiments and facilitated the identification of first in class structural chemotype fragments. With limited resources, we quickly screened fragment 13 and 14 against CDK9 Kinase-Glo assay, and these fragments exhibited 373 and 232 nM potency in inhibiting CDK9. To prove our hypothesis, our idea in developing CDK9 inhibitors for IPF indication, we will synthesize additional 60 analogues of our initial lead OLX-3015, which has excellent potency of 36 nM in inhibiting CK9. In our next steps, we will be working towards mechanistic in vitro and in vivo IPF model studies, in the context of three specific aims. Our proposed Aims 1-3 explicitly addresses (1) Identification of novel, CDK9 selective and orally deliverable CDK9 inhibitors. (2) Inhibition of CDK9 and its associated super-enhancer genes (MCL-1, MYC and cyclic D1) with efficacy in BLM-induced mouse pulmonary fibrosis models and immunotherapeutics effects. (3) The novel chemotype bound specifically to CDK9 and we anticipate high therapeutic outcome with reduce toxicities in IPF patients due to specificity. In summary, the CDK9 is the only one kinase among its members that activates gene expression in a catalyst manner; therefore, Cyclin T/CDK9 is a dedicated kinase functioning in transcription, with inhibiting carboxy-terminal domain (CTD) being the major functional target to achieve clinical benefit IPF patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110170
Entities
People
- Hariprasad Vankayalapati
Organizations
- United States Army