Pharmacokinetic evaluation and comparative omics to decipher the underlining mechanism of newly discovered plant-based androgen receptor targeting small molecules, SKICDDL-1 and SKICDDL-2 against recurrent prostate cancer

Prostate cancer (PCa) is the 2nd leading cause of cancer deaths and primary diagnosed caner in maleswith 1 in 6 men diagnosed with PCa. Projection of burden states that by 2030, 499,000 deathsworldwide will occur due to PCa. By 2021 there will be about 51,979 cases of PCa in India and isexpected to rise by 140% in few years. Androgen receptor is an important ligand dependenttranscription factor (TF) involved in PCa progression, that controls the expression of androgenresponsivegenes. In order to access its target genes, a TF requires localization to the nucleus,restricting this transcription factor in the cytoplasm prevents its activity. Therefore, a crucialregulatory step involved in the action of AR is its nuclear translocation. There is no defined therapyeffectively targeting Androgen Receptor (AR) nuclear localization in PCa. Most of the small moleculesdiscovered against PCa so far cease to act and salvage their survival through PI3K pathway after adefined time and eventually PCa transforms into castration-resistant PCa (CRPC). So, lack of potencyand selectivity, off-target effects as well as poor metabolic stability, are hallmarks of early smallmolecules developed to target PCa and have not shown long-term effects in curing PCa. There is notherapy specifically designed for and capable of effectively targeting AR nuclear localization in CRPCcells. The identification and characterization of novel bioactive molecules inhibiting AR could lead tomore effective and new treatment options for patients with CRPC, including those which relapse aftertreatment. In light of the limitations of the current anticancer drugs, our lab started a drug discoveryprogram in 2016, funded by SERB-ECRA, which led to the discovery of 16 new small molecules againstPCa from medicinal plants. We successfully evaluated two molecules SKCIDDL-1 and SKCIDDL-2 innude mice which showed, lowering of PSA, significant tumor reduction, and doubling of survival innude mice from which we filed 3 patent applications . Since we got an overwhelming response of these two new small molecules,here we propose to evaluate these two molecules for toxicity and biodistribution/pharmacokinetics inmice model and to understand the underlining mechanism of action of these two small molecules.Comparative transcriptomics through RNAseq reveals the pathways that are dysregulated by thesetwo molecules and help us better understand the underlining mechanism of action of these smallmolecules before these are sent for clinical trials and commercialized. The Discovery of newdifferentially expressive proteins will open new vistas for treatment and diagnosis of metastatic PCa.Taken together, it will be interesting and important to develop small molecules capable of effectivelytargeting AR nuclear localization and/or function in CRPC cells.