Research Projects

Pancreatic Ductal Adenocarcinoma (PDAC) a devastating malignancy, with a 11% of 5-year survival rate uses FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) as the first line of treatment in spite of poor overall survival benefits. Other treatment options include Gemcitabine with paclitaxel, PARP Inhibitors (e.g., in the POLO trial), and immunotherapy. However, PDAC is known to be immunologically “cold,” thus benefits are low. Notably, KRAS mutation is a characteristic of ca. 90% PDAC and it often activate NF-κB, a key regulator of inflammation and cell survival, promoting cancer growth and therapy resistance. This context brings us back into the domain of small molecule therapeutic agents where PROTACs (PROteolysis TArgeting Chimera) have brought a paradigm shift in treatment modality. Targeting NF-κB with small molecule inhibitors can potentially enhance the effectiveness in PDAC therapy. Morevoer using dual targeting metal based PROTACs would allow simultaneous targeting of inflammatory signalling and cancer stemness offering a promising therapeutic avenue in PDAC. PROTACs (PROteolysis TArgeting Chimeras) are bifunctional small molecules that induce degradation of specific intracellular proteins by linking them to E3 ubiquitin ligases, promoting ubiquitination and subsequent degradation via the ubiquitin–proteasome system. This paradigm shift to therapeutic approach has led to over 4000 publications and 30 compounds in clinical trials in past ten years. However, leveraging of metal coordination chemistry in PROTACs is scarce in spite of large use and success of Pt-drugs in cancer treatment. There are only four publications so far on metal-based PROTACs (M-PROTACs) and none are from India, highlighting the lacunae and indicating the timeliness of the opportunity for innovation. Our previous findings show that intact pyrazyl-benzimidazole Ru(II) complexes inhibit NF-κB by blocking p65 phosphorylation, nuclear translocation and reduce stemness. We now propose to use this concept of make the protein targeting war head for selective degradation of p65 using rationally designed metal-based PROTACs (M-PROTACs) having E3 ligase binder as the second warhead for ubiquitination and degradation of the target protein. The key point in our innovation is the use of another independently acting compound bound ot the M-PROTAC through a stimuli-responsive cleavable linkers rendering dual-action M-PROTACs. The specific objectives are- (i) Design and Synthesis of a library of Ru(II), Pt(II/IV), and Ir(III)-based M-PROTACs with cleavable linkers and E3 ligase ligands (ii) Evaluate Chemical Stability of the M-PROTAC and stimuli responsive cleavage of the linker (iii) Assess 2D/ 3D organoid based (CSC-enriched) cytotoxicity in PDAC versus normal cells and synergistic effects of the dual action M-PROTACs on cell viability, inflammation, and stemness (iv) Proteomic Profiling to identify targets including downstream one and impact on signalling pathways. (v) Mechanistic Studies to delineate transcriptional vs. post-translational regulation. The novelty and anticipated impact of the work are- (i) These M-PROTACs would not only degrade target proteins but also eliminate proteins that bind and sequester metal drugs, thereby overcoming a key resistance mechanism. (ii) Stimuli-responsive cleavage can block additional oncogenic pathways—such as proliferation, stemness, or metastasis enhancing PDAC treatment efficacy. (iii) Leverage the unique catalytic and coordination properties of metals to design dual-targeting M-PROTACs against PDAC. With fewer than five international reports and none from India, this project will be the first of its kind nationally, fostering innovation, generating potent therapeutic leads, and putting India in the forefront of M-PROTACs research with scope of academia–industry collaboration in M-PORTACs (e.g. with Aurigene oncology).