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New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients' outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29 R , RKO R , SW837 R and HCT116 R , were generated in vitro and validated by IG 50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKO R . AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29 R , SW837 R and HCT116 R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Tamoxifen resistance is a multifaceted phenomenon, characterized by the constitutive activation of multiple signaling cascades that provide an additional survival advantage to cells. Ground studies related to reverse the tamoxifen resistance by employing chemotherapeutic drugs that specifically inhibit proteins, those of aberrantly expressed, are required. Seminal studies showed that p38 signaling and VEGF play crucial role in acquiring resistance to tamoxifen. In this view, we had chosen paclitaxel, a mitotic inhibitor with anti-proliferative effects against a wide array of cancers in this study. Further to mitigate the undesirable complications of paclitaxel (PAC), we employed this drug in combination along with BI2536 (BI), a PLK inhibitor for this study to sensitize the tamoxifen resistant cells to apoptosis. MCF 7/TAM and T-47D/TAM cells were treated with PAC, BI and in combination (BI-PAC) evaluated for its anticancer activity through apoptotic and western blot analysis. Modulatory effects of BI-PAC on p38 inactivation were affirmed through immunofluorescence and drug potential studies. Results reveal that cells were subjected to apoptosis on drug(s) treatment which was confirmed through cytotoxicity, annexin studies. Further, the anti-proliferative effects of the drug(s) were affirmed through nuclear morphological and TUNEL assays. Immunoblot results revealed the upregulation of proapoptotic Bax, cleaved caspase 9 along with Bcl-2, MDM2, Cox-2, and P-Gly down regulation after 24h drug treatments. Moreover, phospho studies further construed the rationale behind the apoptosis and deduced the inactivation of p38 and NF-κB role in inducing apoptosis in drug treated cells. The efficacy of drug combinations in inactivating p38 was evaluated through drug potential studies. Further, BI-PAC treatments showed inhibition of p38 mediated senescence in tamoxifen resistant cells. Overall, our observations provide a new therapeutic combination that sensitizes tamoxifen resistant cells to apoptosis by specifically targeting p38 signaling and its downstream molecules and subsequently reduces extracellular VEGF levels., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)