Arun Sharma, PhD - Penn State Cancer Institute
Researcher Profile
Arun Sharma, PhD
Professor, Department of Pharmacology
Associate Professor, Department of Pharmacology
Associate Professor, Department of Pharmacology
Scientific Program:Next-Generation Therapies
Research Interests
The major focus of Dr. Arun Sharma’s lab is the design and development of novel small drug-like molecules as potential cancer therapeutic and preventive agents, and testing them in various in vitro and in vivo cancer models.
This effort has resulted in the development of some potent anti-cancer agents and understanding of their efficacy, toxicity, pharmacokinetics, and mechanisms of action. The main strategies adapted for designing new agents include optimization of
- naturally occurring agents;
- existing drugs or agents that fail in clinical trials; and
- lead compounds obtained from chemical library screening, to enhance potency, bioavailability and therapeutic/chemopreventive index.
An example of natural product optimization includes the development of ISC-4, an isosteric selenium analog of isothiocyanates that occur naturally in cruciferous vegetables. ISC-4 was shown to be a PI3K/Akt pathway inhibitor that effectively inhibited tumor growth in melanoma and colon cancer xenograft models, alone and in combination with standard of care. Further optimization of ISC-4 structure has now led to a dual Akt pathway/topoisomerase II inhibitor NISC-6 as a potential melanoma therapeutic.
Through extensive structure-activity studies based on Selenium-NSAID hybrid molecules, Dr. Sharma’s lab has recently discovered two potent small molecules: Se-Aspirin, published recently and already commercially available; and AS-10, a bis-aspirinyl-selenazolidine analog which has shown great potential as a cancer therapeutic, particularly for pancreatic cancer. p-XS-Asp, another Se-aspirin hybrid molecule developed recently, is orally bioavailable and effective in preventing against NNK induced lung tumorigenesis.
Apart from developing anti-cancer compounds, Dr. Sharma’s lab is also focusing on developing "smart antibiotics." The emphasis is on designing and synthesizing cationic bolaamphiphiles (CABs) as carrier compounds that can transport antisense oligonucleotide (ASO) into C. difficile to selectively target the genetic material in C. difficile.
- Neoplasms
- Therapeutics
- Cell Line
- Growth
- Apoptosis
- Selenium
- Melanoma
- Colorectal Neoplasms
- In Vitro Techniques
- Cycloaddition Reaction
- Peroxisome Proliferator-Activated Receptors
- Pharmaceutical Preparations
Recent Publications
2024
Johnson, H, Narayan, S & Sharma, AK 2024, 'Altering phosphorylation in cancer through PP2A modifiers', Cancer Cell International, vol. 24, no. 1, 11. https://doi.org/10.1186/s12935-023-03193-1
Nakka, S, Raza, A, Chaitanya, KS, Bandaru, NVMR, Chandu, A, Murugesan, S, Devunuri, N, Sharma, AK & Chandrasekhar, KVG 2024, 'Design, synthesis, and biological evaluation of novel quinoxaline aryl ethers as anticancer agents', Chemical Biology and Drug Design, vol. 103, no. 3, e14502. https://doi.org/10.1111/cbdd.14502
Singh, A, Singh, V, Wallis, N, Abis, G, Oberman, F, Wood, T, Dhamdhere, M, Gershon, T, Ramos, A, Yisraeli, J, Spiegelman, VS & Sharma, AK 2024, 'Development of a specific and potent IGF2BP1 inhibitor: A promising therapeutic agent for IGF2BP1-expressing cancers', European Journal of Medicinal Chemistry, vol. 263, 115940. https://doi.org/10.1016/j.ejmech.2023.115940
Morán-Serradilla, C, Plano, D, Sharma, AK & Sanmartín, C 2024, 'Following the Trace of Cyclodextrins on the Selenium and Tellurium Odyssey', International journal of molecular sciences, vol. 25, no. 14, 7799. https://doi.org/10.3390/ijms25147799
Ramos-Inza, S, Morán-Serradilla, C, Gaviria-Soteras, L, Sharma, AK, Plano, D, Sanmartín, C & Font, M 2024, 'Formulation Studies with Cyclodextrins for Novel Selenium NSAID Derivatives', International journal of molecular sciences, vol. 25, no. 3, 1532. https://doi.org/10.3390/ijms25031532
Gowda, K, Raza, A, Vangala, V, Lone, NA, Lin, JM, Singh, JK, Srivastava, SK, Schell, TD, Robertson, GP, Amin, S & Sharma, AK 2024, 'Identification of Novel Isatin Derivative Bearing a Nitrofuran Moiety as Potent Multi-Isoform Aldehyde Dehydrogenase Inhibitor', Molecules, vol. 29, no. 13, 3114. https://doi.org/10.3390/molecules29133114
Johnson, H, Singh, A, Raza, A, Sha, CM, Wang, J, Gowda, K, Shen, Z, Nair, H, Li, C, Dokholyan, NV, Narayan, S & Sharma, AK 2024, 'Identification of a Novel Protein Phosphatase 2A Activator, PPA24, as a Potential Therapeutic for FOLFOX-Resistant Colorectal Cancer', Journal of Medicinal Chemistry, vol. 67, no. 20, pp. 18070-18089. https://doi.org/10.1021/acs.jmedchem.4c01077
Chowdhary, S, Raza, A, Preeti, Kaur, S, Anand, A, Sharma, AK & Kumar, V 2024, 'Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer', Bioorganic Chemistry, vol. 142, 106953. https://doi.org/10.1016/j.bioorg.2023.106953
Krishna Rao, V, Paul, S, Gulkis, M, Shen, Z, Nair, H, Singh, A, Li, C, Sharma, AK, Çağlayan, M, Das, C, Das, B, Kundu, CN, Narayan, S & Guchhait, SK 2024, 'Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents', RSC Medicinal Chemistry, vol. 15, no. 3, pp. 937-962. https://doi.org/10.1039/d3md00648d
Chen, YC, Gowda, K, Amin, S, Schell, TD, Sharma, AK & Robertson, GP 2024, 'Pharmacological agents targeting drug-tolerant persister cells in cancer', Pharmacological Research, vol. 203, 107163. https://doi.org/10.1016/j.phrs.2024.107163
Swati, Raza, A, Chowdhary, S, Anand, A, Shaveta, , Sharma, AK, Kumar, K & Kumar, V 2024, 'Rational Design and Synthesis of Isatin-Chalcone Hybrids Integrated with 1H-1,2,3-Triazole: Anti-Proliferative Profiling and Molecular Docking Insights', ChemMedChem, vol. 19, no. 14, e202400015. https://doi.org/10.1002/cmdc.202400015
Morán-Serradilla, C, Plano, D, Sanmartín, C & Sharma, AK 2024, 'Selenization of Small Molecule Drugs: A New Player on the Board', Journal of Medicinal Chemistry, vol. 67, no. 10, pp. 7759-7787. https://doi.org/10.1021/acs.jmedchem.3c02426
Angulo-Elizari, E, Raza, A, Encío, I, Sharma, AK, Sanmartín, C & Plano, D 2024, 'Seleno-Warfare against Cancer: Decoding Antitumor Activity of Novel Acylselenoureas and Se-Acylisoselenoureas', Pharmaceutics, vol. 16, no. 2, 272. https://doi.org/10.3390/pharmaceutics16020272
2023
Saran, U, Chandrasekaran, B, Tyagi, A, Shukla, V, Singh, A, Sharma, AK & Damodaran, C 2023, 'A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth', Frontiers in Pharmacology, vol. 14, 1150774. https://doi.org/10.3389/fphar.2023.1150774
Zhu, X, Liu, Q, Patterson, AD, Sharma, AK, Amin, SG, Cohen, SM, Gonzalez, FJ & Peters, JM 2023, 'Accumulation of Linoleic Acid by Altered Peroxisome Proliferator-Activated Receptor-α Signaling Is Associated with Age-Dependent Hepatocarcinogenesis in Ppara Transgenic Mice', Metabolites, vol. 13, no. 8, 936. https://doi.org/10.3390/metabo13080936
Saran, U, Chandrasekaran, B, Tyagi, A, Shukla, V, Singh, A, Sharma, AK & Damodaran, C 2023, 'Corrigendum: A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth (Frontiers in Pharmacology, (2023), 14, (1150774), 10.3389/fphar.2023.1150774)', Frontiers in Pharmacology, vol. 14, 1207589. https://doi.org/10.3389/fphar.2023.1207589
Chowdhary, S, Raza, A, Seboletswe, P, Cele, N, Sharma, AK, Singh, P & Kumar, V 2023, 'Cu-promoted synthesis of Indolo[2,3-b]quinoxaline-Mannich adducts via three-component reaction and their anti-proliferative evaluation on colorectal and ovarian cancer cells', Journal of Molecular Structure, vol. 1275, 134627. https://doi.org/10.1016/j.molstruc.2022.134627
Janicki, PK, Singh, A, Sharma, AK & Ruiz-Velasco, V 2023, 'Dissimilar effects of stereoisomers and racemic hydroxychloroquine on Ca2+ oscillations in human induced pluripotent stem cell-derived cardiomyocytes', Physiological reports, vol. 11, no. 14, e15760. https://doi.org/10.14814/phy2.15760
Ramos-Inza, S, Aliaga, C, Encío, I, Raza, A, Sharma, AK, Aydillo, C, Martínez-Sáez, N, Sanmartín, C & Plano, D 2023, 'First Generation of Antioxidant Precursors for Bioisosteric Se-NSAIDs: Design, Synthesis, and In Vitro and In Vivo Anticancer Evaluation', Antioxidants, vol. 12, no. 9, 1666. https://doi.org/10.3390/antiox12091666
Astrain-Redin, N, Sanmartin, C, Sharma, AK & Plano, D 2023, 'From Natural Sources to Synthetic Derivatives: The Allyl Motif as a Powerful Tool for Fragment-Based Design in Cancer Treatment', Journal of Medicinal Chemistry, vol. 66, no. 6, pp. 3703-3731. https://doi.org/10.1021/acs.jmedchem.2c01406
Astrain-Redin, N, Raza, A, Encío, I, Sharma, AK, Plano, D & Sanmartín, C 2023, 'Novel Acylselenourea Derivatives: Dual Molecules with Anticancer and Radical Scavenging Activity', Antioxidants, vol. 12, no. 7, 1331. https://doi.org/10.3390/antiox12071331
Astrain-Redin, N, Talavera, I, Moreno, E, Ramírez, MJ, Martínez-Sáez, N, Encío, I, Sharma, AK, Sanmartín, C & Plano, D 2023, 'Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds', Antioxidants, vol. 12, no. 1, 139. https://doi.org/10.3390/antiox12010139
Preeti, N, Raza, A, Anand, A, Henry, N, Sharma, AK, Roussel, P & Kumar, V 2023, 'Stereo/regio-selective access to substituted 3-hydroxy-oxindoles with anti-proliferative assessment and in silico validation', RSC Advances, vol. 13, no. 41, pp. 28434-28443. https://doi.org/10.1039/d3ra05869g
Chandrasekaran, B, Tyagi, A, Saran, U, Kolluru, V, Baby, BV, Chirasani, VR, Dokholyan, NV, Lin, JM, Singh, A, Sharma, AK, Ankem, MK & Damodaran, C 2023, 'Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7', Frontiers in Pharmacology, vol. 14, 1137783. https://doi.org/10.3389/fphar.2023.1137783
2022
Ramos-Inza, S, Encío, I, Raza, A, Sharma, AK, Sanmartín, C & Plano, D 2022, 'Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: Identification of a Se-indomethacin analog as a potential therapeutic for breast cancer', European Journal of Medicinal Chemistry, vol. 244, 114839. https://doi.org/10.1016/j.ejmech.2022.114839
Singh, A, Singh, V, Wallis, N, Elimelech, O, Oberman, F, Ramos, A, Yisraeli, J, Spiegelman, V & Sharma, A 2022, 'Development of a Novel IGF2BP1 Inhibitor as Metastasis-Specific Therapeutic Agent', European Journal of Cancer, vol. 174, pp. S104-S105. https://doi.org/10.1016/S0959-8049(22)01078-4
Raza, A, Singh, A, Amin, S, Spallholz, JE & Sharma, AK 2022, 'Identification and biotin receptor-mediated activity of a novel seleno-biotin compound that inhibits viability of and induces apoptosis in ovarian cancer cells', Chemico-Biological Interactions, vol. 365, 110071. https://doi.org/10.1016/j.cbi.2022.110071
Raza, A, Johnson, H, Singh, A & Sharma, AK 2022, 'Impact of selenium nanoparticles in the regulation of inflammation', Archives of Biochemistry and Biophysics, vol. 732, 109466. https://doi.org/10.1016/j.abb.2022.109466
DiPasquale, M, Deering, TG, Desai, D, Sharma, AK, Amin, S, Fox, TE, Kester, M, Katsaras, J, Marquardt, D & Heberle, FA 2022, 'Influence of ceramide on lipid domain stability studied with small-angle neutron scattering: The role of acyl chain length and unsaturation', Chemistry and Physics of Lipids, vol. 245, 105205. https://doi.org/10.1016/j.chemphyslip.2022.105205
Cele, N, Awolade, P, Dhawan, S, Khubone, L, Raza, A, Sharma, AK & Singh, P 2023, 'Quinoline–1,3,4-Oxadiazole Conjugates: Synthesis, Anticancer Evaluation, and Molecular Modelling Studies', Polycyclic Aromatic Compounds, vol. 43, no. 7, pp. 6437-6457. https://doi.org/10.1080/10406638.2022.2117205
Singh, A, Raza, A, Amin, S, Damodaran, C & Sharma, AK 2022, 'Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides', Molecules, vol. 27, no. 3, 886. https://doi.org/10.3390/molecules27030886
Irby, RB, Kline, CLB & Sharma, A 2022, Regulation and role of Par-4 in gastrointestinal tumors. in Tumor Suppressor Par-4: Role in Cancer and Other Diseases. Springer International Publishing, pp. 59-68. https://doi.org/10.1007/978-3-030-80558-6_4
Morán-Serradilla, C, Angulo-Elizari, E, Henriquez-Figuereo, A, Sanmartín, C, Sharma, AK & Plano, D 2022, 'Seleno-Metabolites and Their Precursors: A New Dawn for Several Illnesses?', Metabolites, vol. 12, no. 9, 874. https://doi.org/10.3390/metabo12090874
Karelia, DN, Kim, S, Plano, D, Sharma, AK, Jiang, C & Lu, J 2023, 'Seleno-aspirin compound AS-10 promotes histone acetylation ahead of suppressing androgen receptor transcription, G1 arrest, and apoptosis of prostate cancer cells', Prostate, vol. 83, no. 1, pp. 16-29. https://doi.org/10.1002/pros.24430
Narayan, S, Raza, A, Mahmud, I, Koo, N, Garrett, TJ, Law, ME, Law, BK & Sharma, AK 2022, 'Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A', iScience, vol. 25, no. 7, 104518. https://doi.org/10.1016/j.isci.2022.104518
Koo, N, Sharma, AK & Narayan, S 2022, 'Therapeutics Targeting p53-MDM2 Interaction to Induce Cancer Cell Death', International journal of molecular sciences, vol. 23, no. 9, 5005. https://doi.org/10.3390/ijms23095005
2021
Chen, YC, Dinavahi, SS, Feng, Q, Gowda, R, Ramisetti, S, Xia, X, LaPenna, KB, Chirasani, VR, Cho, SH, Hafenstein, SL, Battu, MB, Berg, A, Sharma, AK, Kirchhausen, T, Dokholyan, NV, Amin, S, He, P & Robertson, GP 2021, 'Activating Sphingosine-1-phospahte signaling in endothelial cells increases myosin light chain phosphorylation to decrease endothelial permeability thereby inhibiting cancer metastasis', Cancer Letters, vol. 506, pp. 107-119. https://doi.org/10.1016/j.canlet.2021.01.004
Lee, SY, Slagle-Webb, B, Sharma, AK & Connor, JR 2021, 'Biological activity of a thiobarbituric acid compound in neuroblastomas', Anticancer Research, vol. 41, no. 3, pp. 1171-1181. https://doi.org/10.21873/anticanres.14874
Foreman, JE, Koga, T, Kosyk, O, Kang, BH, Zhu, X, Cohen, SM, Billy, LJ, Sharma, AK, Amin, S, Gonzalez, FJ, Rusyn, I & Peters, JM 2021, 'Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPARα Agonist in PPARA-Humanized Mice', Toxicological Sciences, vol. 183, no. 1, pp. 70-80. https://doi.org/10.1093/toxsci/kfab067
Bapat, P, Sewell, DG, Boylan, M, Sharma, AK & Spallholz, JE 2021, 'In vitro cytotoxicity of trastuzumab (Tz) and se-trastuzumab (se-tz) against the her/2 breast cancer cell lines jimt-1 and bt-474', International journal of molecular sciences, vol. 22, no. 9, 4655. https://doi.org/10.3390/ijms22094655
Ramos-Inza, S, Ruberte, AC, Sanmartín, C, Sharma, AK & Plano, D 2021, 'NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention-Structural Modulation, Mechanisms of Action, and Bright Future', Journal of Medicinal Chemistry, vol. 64, no. 22, pp. 16380-16421. https://doi.org/10.1021/acs.jmedchem.1c01460
Karelia, DN, Kim, S, Pandey, MK, Plano, D, Amin, S, Lu, J & Sharma, AK 2021, 'Novel seleno-aspirinyl compound as-10 induces apoptosis, g1 arrest of pancreatic ductal adenocarcinoma cells, inhibits their nf-κb signaling, and synergizes with gemcitabine cytotoxicity', International journal of molecular sciences, vol. 22, no. 9, 4966. https://doi.org/10.3390/ijms22094966
Wallis, N, Oberman, F, Shurrush, K, Germain, N, Greenwald, G, Gershon, T, Pearl, T, Abis, G, Singh, V, Singh, A, Sharma, AK, Barr, HM, Ramos, A, Spiegelman, VS & Yisraeli, JK 2022, 'Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells', RNA Biology, vol. 19, no. 1, pp. 26-43. https://doi.org/10.1080/15476286.2021.2010983
Foreman, JE, Koga, T, Kosyk, O, Kang, BH, Zhu, X, Cohen, SM, Billy, LJ, Sharma, AK, Amin, S, Gonzalez, FJ, Rusyn, I & Peters, JM 2021, 'Species Differences between Mouse and Human PPARα in Modulating the Hepatocarcinogenic Effects of Perinatal Exposure to a High-Affinity Human PPARα Agonist in Mice', Toxicological Sciences, vol. 183, no. 1, pp. 81-92. https://doi.org/10.1093/toxsci/kfab068
2020
Tyagi, A, Sharma, AK & Damodaran, C 2020, 'A Review on Notch Signaling and Colorectal Cancer', Cells, vol. 9, no. 6, 1548. https://doi.org/10.3390/cells9061549
Tyagi, A, Kolluru, V, Chandrasekaran, B, Saran, U, Sharma, AK, Ankem, MK & Damodaran, C 2020, 'ASR488, a novel small molecule, activates an mRNA binding protein, CPEB1, and inhibits the growth of bladder cancer', Oncology Letters, vol. 20, no. 1, pp. 850-860. https://doi.org/10.3892/ol.2020.11593
Tyagi, A, Chandrasekaran, B, Kolluru, V, Baby, BV, Sripathi, CA, Ankem, MK, Ramisetti, SR, Chirasani, VR, Dokholyan, NV, Sharma, AK & Damodaran, C 2020, 'ASR490, a small molecule, overrides aberrant expression of notch1 in colorectal cancer', Molecular cancer therapeutics, vol. 19, no. 12, pp. 2422-2431. https://doi.org/10.1158/1535-7163.MCT-19-0949
Gütschow, M, Eynde, JJV, Jampilek, J, Kang, CB, Mangoni, AA, Fossa, P, Karaman, R, Trabocchi, A, Scott, PJH, Reynisson, J, Rapposelli, S, Galdier, S, Winum, JY, Brullo, C, Prokai-Tatrai, K, Sharma, AK, Schapira, M, Azuma, YT, Cerchia, L, Spete, M, Torri, G, Collina, S, Geronikaki, A, García-Sosa, AT, Helena Vasconcelos, M, Sousa, ME, Kosalec, I, Tuccinardi, T, Duarte, IF, Salvador, JAR, Bertinaria, M, Pellecchia, M, Amato, J, Rastelli, G, Gomes, PAC, Guedes, RC, Sabatier, JM, Estévez-Braun, A, Pagano, B, Mangani, S, Ragno, R, Kokotos, G, Brindisi, M, González, FV, Borges, F, Miloso, M, Rautio, J & Muñoz-Torrero, D 2020, 'Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-7', Molecules, vol. 25, no. 13, 2968. https://doi.org/10.3390/molecules25132968
Lee, SY, Slagle-Webb, B, Sharma, AK & Connor, JR 2020, 'Characterization of a novel barbituric acid and two thiobarbituric acid compounds for lung cancer treatment', Anticancer Research, vol. 40, no. 11, pp. 6039-6049. https://doi.org/10.21873/anticanres.14625
Ruberte, AC, González-Gaitano, G, Sharma, AK, Aydillo, C, Encío, I, Sanmartín, C & Plano, D 2020, 'New formulation of a methylseleno-aspirin analog with anticancer activity towards colon cancer', International journal of molecular sciences, vol. 21, no. 23, 9017, pp. 1-17. https://doi.org/10.3390/ijms21239017
Gummidi, L, Kerru, N, Awolade, P, Raza, A, Sharma, AK & Singh, P 2020, 'Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents', Bioorganic and Medicinal Chemistry Letters, vol. 30, no. 22, 127544. https://doi.org/10.1016/j.bmcl.2020.127544
Annageldiyev, C, Tan, SF, Thakur, S, Dhanyamraju, PK, Ramisetti, SR, Bhadauria, P, Schick, J, Zeng, Z, Sharma, V, Dunton, W, Dovat, S, Desai, D, Zheng, H, Feith, DJ, Loughran, TP, Amin, S, Sharma, AK, Claxton, D & Sharma, A 2020, 'The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia', Frontiers in Oncology, vol. 10, 393. https://doi.org/10.3389/fonc.2020.00393
Ruberte, AC, Aydillo, C, Sharma, AK, Sanmartín, C & Plano, D 2020, 'Vilsmeier reagent, NaHSe and diclofenac acid chloride: One-pot synthesis of a novel selenoindolinone with potent anticancer activity', RSC Advances, vol. 10, no. 63, pp. 38404-38408. https://doi.org/10.1039/d0ra07332f