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)…
Researchers have developed artificial, computer-generated multitarget-directed ligands (MTDLs) to treat refractory diseases, particularly cancer. In this study, they focused on endometrial adenocarcinoma (EAC), a type of cancer. Through in silico design, they discovered a novel synthetic lethality in EAC linked to PTEN loss of function (LOF) and the inhibition of CDK9, a type of kinase enzyme.
Using high-resolution x-ray crystallographic data, scientists chemically engineered a molecule called LCI133. This molecule targets multiple kinases, including CDK9, CDK4/6, and AURKA/B. The research indicates that PTEN LOF in EAC cells leads to increased deregulated transcription and a significant rise in nascent RNA, making these cells more susceptible to LCI133 treatment and other CDK9 inhibitors.
LCI133 treatment results in a sharp decline in overall ribonucleic acid (RNA) levels, MYC RNA levels, and TE (telomere elongation) in PTEN LOF EAC cells. The study confirms that PTEN LOF is both necessary and sufficient to make EAC cells sensitive to LCI133 and other CDK9 inhibitors.
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