In silico engineered multitarget-directed ligands for the polypharmaceutical treatment of PTEN loss of function endometrial adenocarcinoma

To combat refractory diseases, such as cancer, multitarget-directed ligands (MTDLs) have become an emerging area of research to exploit synthetic lethality (SL) relationships associated with drug resistance. Herein, we present the in silico design of MTDLs for the polypharmaceutical treatment of endometrial adenocarcinoma (EAC) and our discovery of a novel SL in EAC; PTEN loss of function (LOF) and the inhibition of CDK9. We used high-resolution x-ray crystallographic data to chemically engineer, LCI133, to inhibit CDK9, CDK4/6-and AURKA/B kinases. PTEN LOF in EAC results in augmented deregulated transcription and a massive increase in nascent RNA, a phenotype which encodes a high level of apoptotic sensitivity to LCI133 and CDK9 inhibitors. Treatment with LCI133 results in a rapid decline " nose-dive " in global nRNA, MYC nRNA levels and TS elongation (TE) in PTEN LOF EAC. PTEN LOF is necessary and sufficient to confer sensitivity of EAC cells to LCI133 and other CDK9 inhibitors.

To exploit a novel pharmacologic SL, we in silico engineered the highly selective triple-action small molecule CDK9-CDK4/6-AURKA/B inhibitor, LCI133 which induces cancer cell death selectively in PTEN LOF EAC cells, an effect causally linked to PTEN loss of function, CDK9 inhibition and its associated deregulated/augmented TS elongation phenotype, transcriptional addiction (TA).

Schematic diagram shows the rationale for the intentional in silico design of the triple inhibitory chemotype, LCI133 to block three selective clinically relevant targets in PTEN mutated EAC to in vivo perturb the cell cycle, transcription (TS) and mitosis in same cancer cell at the same time (SL).