Sahil Sharma

Senior Research Scientist

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Sahil Sharma

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.

Publications

Research Papers

  1. Sharma, S.; Kalidindi, T.; Joshi, S.; Digwal, C. S.; Panchal, P.; Burnazi, E.; Lee, S. G.; Pillarsetty, N.; Chiosis, G. Synthesis of 124I-labeled epichaperome probes and assessment in visualizing pathologic protein-protein interaction networks in tumor bearing mice. STAR Protocols 2022, 3, 101318.
  2. Singh, J. V.; Thakur, S.; Kumar, N.; Singh, H.; Mithu, V. S.; Singh, H.; Bhagat, K.; Gulati, H.; Sharma, A.; Singh, H.; Sharma, S; Bedi, P. M. S. Donepezil inspired multi-targeting indanone derivatives as effective anti-Alzheimer’s agents. ACS Chem Neurosci 2022, 13, 733–750.
  3. Joshi, S.; Gomes, E. D.; Wang, T.; Corben, A.; Taldone, T.; Gandu, S.; Chao Xu, C.; Sharma, S.; Buddaseth, S.; Yan, P.; Chan, L. Y. L.; Gokce, A.; Rajasekhar, V. K.; Shrestha, L.; Panchal, P.; Almodovar, J.; Digwal, C.; Rodina, A.; Pillarsetty, N.; Miclea, V.; Peter, R. I.;, S. D.; Tang, L.; Mattar, M.; de Stanchina, E.; Yu, K. H.; Lowery, M.; Grbovic-Huezo, O.; O’Reilly, E. M.; Janjigian, Y.; Healey, J. H.; Jarnagin, W. R.; Allen, P. J.; Sander, C.; Erdjument-Bromage, H.; Neubert, T. A.; Leach, S. D.; Chiosis, G. Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer. Commun Biol 2021, 4,1333.
  4. Bolaender, A.#; Zatorska, D.#; He, H.#; Joshi, S.#; Sharma, S.#; Digwal, C. S.#; Patel, H. J.; Sun, W.; Imber, B. S.; Ochiana, S. O.; Patel, M. R.; Shrestha, L.; Shah, S. K.; Wang, S.; Karimov, R.; Tao, H.; Patel, P.D.; Martin, A. R.; Yan, P.; Panchal, P.; Almodovar, J.; Corben, A.; Rimner, A.; Ginsberg, S. D.; Lyashchenko, S.; Burnazi, E.; Ku, A.; Kalidindi, T.; Lee, S. G.; Grkovski, M.; Beattie, B. J.; Zanzonico, P.; Lewis, J. S.; Larson, S.; Rodina, A.; Pillarsetty, N.; Tabar, V.; Dunphy, M. P.; Taldone, T.; Shimizu, F.; Chiosis, G. Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system. Nat Commun 2021, 12, 4669.
  5. Sugita, M.; Wilkes, D. C.; Bareja, R.; Eng, K. W.; Nataraj, S.; Jimenez-Flores, R. A.; Yan, L.; De Leon, J. P.; Croyle, J. A.; Kaner, J.; Merugu, S.; Sharma, S.; MacDonald, T. Y.; Noorzad, Z.; Panchal, P.; Pancirer, D.; Cheng, S.; Xiang, J. Z.; Olson, L.; Besien, K. V.; Rickman, D. S.; Mathew, S.; Tam, W.; Rubin, M. A.; Beltran, H.; Sboner, A.; Hassane, D. C.; Chiosis, G.; Elemento, O.; Roboz, G. J.; Mosquera, J. M.; Guzman, M. L. Targeting the Epichaperome As an Effective Precision Medicine Approach in a Novel PML-SYK Fusion Acute Myeloid Leukemia. NPJ Precis Oncol 2021, 5, 44.
  6. Singh, A.; Sharma, S.; Arora, S.; Attri, S.; Kaur, P.; Gulati, H. K.; Bhagat, K.; Kumar, N.; Singh, H.; Singh, J. V.; Bedi, P. M. S. New coumarin-benzotriazole based hybrid molecules as inhibitors of acetylcholinesterase and amyloid aggregation. Bioorg Med Chem Lett 2020, 30, 127477.
  7. Yan, P.; Patel, H. J.; Sharma, S.; Corben, A.; Wang, T.; Panchal, P.; Yang, C.; Sun, W.; Araujo, T. L.; Rodina, A.; Joshi, S.; Robzyk, K.; Gandu, S.; White, J. R.; de Stanchina, E.; Modi, S.; Janjigian, Y. Y.; Hill, E. G.; Liu, B.; Erdjument-Bromage, H.;  Neubert, T. A.; Que, N. L. S.; Li, Z.; Gewirth, D. T.; Taldone, T.; Chiosis, G. Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone. Cell Rep 2020, 31, 107840.
  8. Pechalrieu, D.; Assemat, F.; Halby, L.; Marcellin, M.; Yan, P.; Chaoui, K.; Sharma, S.; Chiosis, G.; Burlet-Schiltz, O.; Arimondo, P. B.; Lopez, M. Bisubstrate-Type Chemical Probes Identify GRP94 as a Potential Target of Cytosine-Containing Adenosine Analogs. ACS Chem Biol 2020, 15, 952-961.
  9. Kaur, G.; Singh, J. V.; Gupta, M. K.; Bhagat, K.; Gulati, H. K.; Singh, A.; Bedi, P. M. S.; Singh, H.; Sharma, S*. Thiazole-5 carboxylic acid derivatives as potent xanthine oxidase inhibitors: design, synthesis, in vitro evaluation, and molecular modeling studies. Med Chem Res 2020, 29, 83-93.
  10. Bhagat, K.; Singh, A.; Dhiman, S.; Singh, J. V.; Kaur, R.; Kaur, G.; Gulati, H. K.; Singh, P.; Kumar, R.; Salwan, R.; Bhagat, K.; Singh, H.; Sharma, S.*; Bedi, P. M. S. Microwave-assisted synthesis of 11-substituted-3,3-dimethyl-2,3,4,5,10,11-hexahydrodibenzo[b,e][1,4]diazepin-1-onederivatives catalysed by silica supported fluoroboric acid as potent antioxidant and anxiolytic agents. Med Chem Res 2019, 28, 2200-2217.
  11. Singh, A.; Singh, J. V.; Rana, A.; Bhagat, K.; Gulati, H. K.; Kumar, R.; Salwan, R.; Bhagat, K.; Kaur, G.; Singh, N.; Kumar, R.; Singh, H.; Sharma, S.*; Bedi, P. M. S. Monocarbonyl curcumin based molecular hybrids as potent antibacterial agents. ACS Omega 2019, 4, 11673-11684.
  12. Huck, J. D.; Que, N. L. S.; Sharma, S.; Taldone, T.; Chiosis, G.; Gewirth, D. T. Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity. Proteins 2019, 87, 869-877.
  13. Bhagat, K.; Bhagat, J.; Gupta, M. K.; Singh, J. V.; Gulati, H. K.; Singh, A.; Kaur, K.; Kaur, G.; Sharma, S.; Rana, A.; Singh, H.; Sharma, S.*; Bedi, P. M. S. Design, Synthesis, Antimicrobial Evaluation, and Molecular Modeling Studies of Novel Indolinedione-Coumarin Molecular Hybrids. ACS Omega 2019, 4, 8720-8730.
  14. Singh, J. V.; Kaur, G.;Gupta, M. K.;Singh, A.;Nepali, K.;Singh, H.; Sharma, S.*; Bedi, P. M. S. Benzoflavone derivatives as potent antihyperuricemic agents. Med Chem Comm 2019, 10, 128-147.
  15. Joshi, G.; Wani, A. A.; Sharma, S.; Bhutani, P.; Bharatam, P. V.; Paul, A. T.; Kumar, R. Unanticipated Cleavage of 2‑Nitrophenyl-Substituted N‑Formyl Pyrazolines under Bechamp Conditions: Unveiling the Synthesis of 2‑Aryl Quinolines and Their Mechanistic Exploration via DFT Studies. ACS Omega 2018, 3, 18783−18790.
  16. Singh, H.; Singh, H.; Singh, A.; Gupta, M. K.; Sharma, S.*; Bedi, P. M. S. Microwave Assisted SiO2-H2SO4 Catalyzed Synthesis of 3,4,6,7-Tetrahydro-3,3,6,6-Tetra Methyl-9,10-Diphenylacridine-1,8-Dione derivatives as cholesterol esterase Inhibitors. Ind J Pharm Sci 2017, 79, 801–812.
  17. Shrestha, L.; Patel, H. J.; Kang, Y.; Sharma, S.; Chiosis, G.; Taldone, T. Copper Mediated Coupling of 2-(Piperazine)-pyrimidine Iodides with Aryl Thiols using Cu (I) Thiophene-2-carboxylate. Tetrahedron Lett 2017, 58, 4525–4531.
  18. Singh, H.; Singh, J. V.; Gupta, M. K.; Saxena, A. K.; Sharma, S.*; Nepali, K.; Bedi, P. M. S. Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies. Bioorg Med Chem Lett 2017, 27, 3974–3979.
  19. Singh, H.; Singh, J. V.; Gupta, M. K.; Singh, P.; Sharma, S.*; Nepali, K.; Bedi, P. M. S. Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies. Bioorg Med Chem Lett 2017, 27, 850-854.
  20. Kaur, M.; Kaur, A.; Mankotia, S.; Singh, H.; Singh, A.; Singh, J. V.; Gupta, M. K.; Sharma, S.*; Nepali, K.; Bedi, P. M. S. Synthesis, screening and docking of fused pyrano[3,2-d]pyrimidine derivatives as xanthine oxidase inhibitor. Eur J Med Chem 2017, 131, 14-28.
  21. Singh, H.; Singh, J. V.; Gupta, M. K.; Singh, P.; Sharma, S.*; Nepali, K.; Bedi P. M. S. Benzoflavones as cholesterol esterase inhibitors: Synthesis, biological evaluation and docking studies. Bioorg Med Chem Lett 2017, 27, 850-854.
  22. Sharma, S.; Gupta, M. K.; Saxena A. K.; Bedi, P. M. S. Thiazolidinone Constraint Combretastatin Analogs as Novel Antitubulin Agents: Design, Synthesis, Biological Evaluation and Docking Studies. Anticancer Agents Med Chem 2017, 17, 230-240.
  23. Singh, H.; Kumar, M.; Nepali, K.; Gupta, M. K.; Saxena, A. K.; Sharma, S.*; Bedi, P. M. S. Triazole tethered C5-curcuminoid-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies. Eur J Med Chem 2016, 116, 102-115.
  24. Sharma, S.; Gupta, M. K.; Saxena, A. K.; Bedi, P. M. S. Triazole linked mono carbonyl curcumin- isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies. Bioorg Med Chem 2015, 23, 7165-7180.
  25. Kaur, C.; Dhiman, S.; Singh, H.; Kaur, M.; Bhagat, S.; Gupta, M. K.; Sharma, S.*; Bedi, P. M. S. Synthesis, screening and docking studies of benzochromone derivatives as xanthine oxidase inhibitors. J Chem Pharm Res 2015, 7, 127-136.
  26. Singh, J. V.; Sharma, S.*; Rahar, S. Synthesis and spermicidal activity of substituted (E)-3- (aryl/heteroaryl)-1-phenylprop-2-en-1-ones. Der Pharma Chem 2015, 7, 93-103.
  27. Kaur, R.; Naaz, F.; Sharma, S.; Mehndiratta, S.; Gupta, M. K.; Bedi , P. M. S.; Nepali, K. Screening of a library of 4-Aryl/Heteroaryl-4H-fused pyrans for xanthine oxidase inhibition: Synthesis, biological evaluation and docking studies. Med Chem Res 2015, 24, 3334–3349.
  28. Sharma, S.; Kaur, C.; Budhiraja, A.; Nepali, K.; Gupta, M. K.; Saxena, A. K.; Bedi, P. M. S. Chalcone based azacarboline analogues as novel antitubulin agents: Design, synthesis, biological evaluation and molecular modeling studies. Eur J Med Chem 2014, 85, 648-660.
  29. Sharma, S.; Sharma, K.; Ojha, R.; Kumar, D.; Singh, G.; Nepali K.; Bedi ,P. M. S. Microwave assisted synthesis of naphthopyrans catalysed by silica supported fluoroboric acid as a new class of non-purine xanthine oxidase inhibitors. Bioorg Med Chem Lett 2014, 24, 495–500.
  30. Singh, H.; Sharma, S.; Ojha, R.; Gupta, M. K.; Nepali, K.; Bedi, P. M. S. Synthesis and evaluation of naphthoflavones as a new class of non-purine xanthine oxidase inhibitors. Bioorg Med Chem Lett 2014, 24, 4192–4197.
  31. Virdi, H. S.; Sharma, S.; Mehndiratta, S; Bedi, P. M. S.; Nepali, K. Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors. J Enzyme Inhib Med Chem 2014, 30, 1-7.
  32. Sharma, M.; Sharma, S.; Buddhiraja, A.; Saxena, A. K.; Nepali, K.; Bedi, P. M. S. Synthesis and cytotoxicity studies of 3,5-diaryl N-acetyl pyrazoline-isatin hybrids. Med Chem Res 2014, 23, 4337- 4344.
  33. Sharma, S.; Thakur, V.; Ojha, R.; Budhiraja, A.; Nepali, K.; Bedi, P. M. S. Aza Analogs of Flavones as Potential Antimicrobial Agents. Lett Drug Des Discov 2013, 10, 327-334.
  34. Singh, J.; Sharma, S.; Saxena, A. K.; Nepali, K.; Bedi, P. M. S. Synthesis of 1,2,3-triazole tethered bifunctional hybrids by click chemistry and their cytotoxic studies. Med Chem Res 2013, 22, 3160- 3169.
  35. Dhiman, R.; Sharma, S.; Singh, G.; Nepali, K.; Bedi , P. M. S. Design and Synthesis of Aza-Flavones as a New Class of Xanthine Oxidase Inhibitors. Arch Pharm Chem Life ScI 2013, 346, 7–16.