I received my Ph.D. in Pharmaceutical Chemistry from Guru Nanak Dev University, Amritsar, Punjab, India. During my doctoral studies, I have synthesized several libraries of heterocyclic molecules with anti-tubulin and xanthine oxidase inhibitory activity that can be useful in cancer and gout, respectively. These compounds were either rationally designed using a molecular hybridization approach based on the combination of pharmacophoric moieties of different bioactive substances to produce new hybrid compounds with improved affinity and efficacy or natural product-inspired scaffolds. An extensive library of compounds was synthesized and evaluated in several in vitro and in vivo assays designed to measure anti-tubulin activity and inhibition of xanthine oxidase. These results led to the discovery of novel compounds such as tubulin and xanthine oxidase inhibitors. Further to reveal their mechanisms to act as potent enzyme inhibitors, molecular modeling studies were also performed which helped me to rationalize their binding pattern within the enzyme’s active sites.
Currently, I am working as a Senior Research Scientist in the laboratory of Dr. Gabriela Chiosis at MSKCC. Being an experienced medicinal chemist, I use a chemical biology approach to understand, diagnose, and treat cellular processes associated with chronic stress, with the goal of developing novel therapeutic options for the treatment of human diseases. In this regard, my expertise in designing and synthesizing small molecule inhibitors as well as biological probes for these targets has been critical to the successful outcomes of our research projects. I have extensive knowledge of chemistry and its proper application for establishing structure-activity relationships (SAR) as well as a keen understanding of what is required to transform a molecule into a drug. I have also acquired knowledge of disease biology with the belief that it is biology that drives the successful development of any drug discovery program. I believe that my qualifications and experience to date put me in a position to uniquely impact the field and potentially provide treatments for cancer and neurodegenerative diseases.
In this capacity, I investigate the role of chaperones such as HSP90, HSP70, and GRP94 in various diseases including cancer and neurodegeneration. My prime focus is the rational development of small molecule anticancer therapeutics that target heat shock protein 70 (HSP70). I am involved in the optimization of the potency and the physicochemical properties of HSP70 inhibitors. In parallel with our rational strategy to generate allosteric HSP70 inhibitors and their preclinical testing in several xenograft mice models, we also perform pharmacokinetic studies and formulation development with the goal of designing a small molecule that can be transitioned into the clinic for evaluation in humans. I am also involved in the development of several chemical tools that are being used to investigate the biological details of HSP70 networks in cancer cells.
I am also working towards the development of selective GRP94 (ER paralog of HSP90) inhibitors for the treatment of cancer. In this regard, my research has focused on the design, synthesis, and biological characterization of potent and selective inhibitors of hyperglycosylated Glucose Regulated Protein 94 (hgGRP94). GRP94 is a chaperone protein that plays an important role in protein folding and maintaining ER quality. GRP94, however, has been shown to be important for tumor survival and helps regulate the stability of plasma membrane-bound receptor tyrosine kinases (RTKs) to maintain their oncogenic properties. Previously, our lab has shown that specific inhibition of hgGRP94 is feasible in cancer and has identified a series of highly selective ligands. The goal of my project is to advance these ligands to clinical leads that target hgGRP94 and identify those tumors sensitive to inhibition. Towards this, with the aid of structure-based drug design, a library of small molecules will be synthesized and characterized using various in vitro assays with promising candidates leading to in vivo studies. I am also involved in the synthesis of several chemical biology tools that have been instrumental in elucidating novel mechanisms associated with hgGRP94 in RTK overexpressing cancer cells.
My research also involves the rational development of compounds that selectively target aberrant HSP90 networks, which are present as multi-chaperone complexes in cancer cells and play a critical role in the development of cancer and potentially other diseases. One of the aims of my project is to develop fluorescent probes that target these oncogenic HSP90 networks and can be used for intraoperative visualization of cancer cells during surgical procedures. Since surgical removal of operable tumors remains the gold standard of care in the treatment of many tumors, a method for the detection of the extent of malignancy is key for an optimal surgical outcome and to reduce surgery-related complications.