Rational Design of First-In-Class Dual Parp-Syk Inhibitors as Antitumor Agents

This proposal aims to extract amplified antitumor effects via one scaffold - two target approach (dual PARP-SYK). The successful execution of the attempts strategized in this study can strengthen the candidature of bifunctional PARP therapeutics as antitumor agents. Noteworthy to mention that PARP-1 inhibitors as single target drugs, in the recent past, have experienced a notable reluctance from researchers to utilize them as chemotherapeutics, owing to their narrow therapeutic spectrum entailed by synthetic lethality coupled with resistance issues. Thus, a positive outcome of this proposal can provide a prudent tactic to the medicinal chemist for expanding the activity spectrum of PARP-1 inhibitors, thereby enhancing their therapeutic utility. Noteworthy to mention that, at present, the academicians working in the field of antitumor drug discovery are in a transition state, in terms of transposing their inclination from single target therapeutics to dual inhibitors, PROTACS, antibody-drug conjugates and others. In this context, the medicinal chemist and the biologist are eagerly trying to accumulate shreds of evidence/ valid reasons that can advocate for the superiority of the latter approaches (dual inhibitors, PROTACS, antibody-drug conjugates) over the former (single target agents). Thus, this proposal holds enough optimism, particularly in light of the promising preliminary results, to provide a ray of hope to the academicians, convincing them to invest their efforts in this direction. To add on, the positive outcome of this proposed investigation may imbibe a high degree of fascination among the budding and brightest science graduates towards the various scaffold construction approaches as well as structural engineering strategies. Overall, the long-run attempts are focused on extracting societal benefits through this research endeavour for the academicians, researchers, young scientists and the pharmaceutical industrial sector.