Tankyrase, Poly (ADP-ribose) polymerase5 (PARP5), a member of PARP protein superfamily, is an emerging novel target for the treatment of colon, breast, bladder, gastric cancers etc. It plays a key role in Wnt signaling which is an essential pathway for adult homeostasis and embryonic development like regeneration of skin, gut, hair and bone marrow. It has been observed that Wnt and their downstream effectors are directly or indirectly involved in tumor initiation, growth, and metastasis. Tankyrase is the enzyme which controls the level of Axin, one of the key component of Wnt signaling. Inhibition of tankyrase activity promotes Axin stabilization and attenuates Wnt signaling in cancer cells which in turn controls cell proliferation and/or metastasis of cancer. During the past few years, there has been an increased interest in the development of selective small-molecular tankyrase inhibitors and few molecules are currently in the preclinical phase. To design such new molecules, in-silico pharmacophore modeling (DISCOTech Module, SybylX), 3D-QSAR (CoMFA and CoMSIA), virtual screening, molecular docking (Surflex, SybylX) and ADMET prediction (OSIRIS property explorer) studies were performed to identify potential hits which could be optimized into leads and further synthesized. Based on the results of computational studies, a series of substituted quinazolin-4-one was synthesized and characterized. In-vitro cell viability MTT assay was performed to screen all the synthesized molecules against APC wild-type (HCT116) and APC mutant (SW480, SW620, HT29) colon cancer cell lines using doxorubicin as standard. Compound AP-9 and AP-10 gave best results in APC mutant SW480 cell line with IC50 40.23 μM and 43.45 μM respectively which was found better than doxorubicin (IC50 64.05 μM). Further in-vitro studies of both the compounds are under progress.

Rational design, synthesis, and in-vitro screening of novel tankyrase inhibitors for the treatment of cancer

2019 Spring National Meeting

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