Abstract

AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. C-Met Inhibitor MK-8003 Radiosensitizes c-Met-Expressing Non-Small Cell Lung Cancer Cells with Radiation-Induced c-Met-Expression. In this study we for the first time designed small-molecule PUMA derived peptide mimetic inhibitors for mitigating a potential radiation-induced cell death. These chemical recored scaffolds are consisting of linked small pharmaco-fragments and DNA-induced nucleic acid mimicking molecules that may interact with the DNA double-strand breaks (called Dbait) and would possible in the future act as a disorganizing damage signaling and DNA repair druggable compound. We in silico analyzed the fitness scoring results and the pharmaco-docking free energy binding effects of our synthetic mimotopic Dbait lignads in conserved DNA mutant regions responsible for the tumor growth and performed preliminary ligand structure based QSAR studies of their mechanism(s) of action. Here, in Biogenea we finally in silico multi-molecularly targeted conserved Radiosensitization regions of Human Cancer binding domains by Modulating Inhibitor of apoptosis purpose for the potentiating of a future enhanced DNA repair activity which is often associated with tumor resistance to radiotherapy. Although many radiosensitizers have been developed, their clinical benefit is hampered by a failure to improve the therapeutic ratio due to a lack of tumor specific delivery over normal tissue. We propose to utilize drug conjugated activatable cell penetrating peptides (ACPP) as tumor selective delivery vehicles for the in silico of a fragment ligand based novel multitargeted potent radiosensitizers. Cyclic RGD pretargeted ACPP (ACPP-RGD) are selectively cleaved and activated in the tumor microenvironment through tumor associated matrix metalloproteinase activity and RGD binding integrins.In this in silico, study we finally have for the first time algorithmically discovered Small-Molecule PUMA targeted (ACPP-RGD)-Nutlin-3-AT-101 Inhibitors for Mitigating Radiation-Induced Cell Death generating a compouter KNIME-assisted platform novel synthetic of radiosensitizer.