Photo of Jose A. Halperin,  MD

Jose A. Halperin, MD

Harvard Medical School

Harvard Medical School
Phone: (617) 621-6136
Fax: (617) 621-6148

Jose A. Halperin, MD

Harvard Medical School


  • Associate Professor, Medicine, Harvard Medical School


Research Abstract

My cancer research originated with the discovery of the anticancer effect of the anti-fungal drug clotrimazole (CLT). I found that CLT has a dual effect on intracellular calcium: it releases clacium from internal stores and closes restorative calcium influx. The resulting partial depletion of internal calcium activates the enzyme PKR, which phosphorylates and thereby inhibits eukaryotic initiation factor 2, the first step in mRNA translation initiation. In this manner, CLT inhibits translation initiation and synthesis of a subset of proteins that includes cyclin D1 and E, and stops cell cycle progression in the G1. My identification of the pharmacophore responsible for this anti-cancer effect of CLT has led to the rational design of analogs that are more potent and less toxic inhibitors of translation initiation.

My laboratory's most recent finding is that the n-3 unsaturated fatty acid EPA as well as thiazoinianones (TZDs) have anti-cancer effects that are mediated by inhibition of translation initiation in a manner almost identical to the effect of CLT. This is potentially important because epidemiological studies have shown that populations eating fish diets rich in EPA exhibit a very low incidence of cnacer, and the TZDs have already been tested in clinical trials for human cancers.

In summary, my cancer research has led to the uncovering of translation initiation as a valid target for anticancer drugs and to the discovery of new inhibitors of translation initiation soon to be tested in humans.


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  • Aktas BH, Bordelois P, Peker S, Merajver S, Halperin JA. Depletion of eIF2·GTP·Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo. 2015. PubMed
  • Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA, Wagner G. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A 2014; 111:E3187-95. PubMed
  • Mahalingam P, Takrouri K, Chen T, Sahoo R, Papadopoulos E, Chen L, Wagner G, Aktas BH, Halperin JA, Chorev M. Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction. J Med Chem 2014. PubMed
  • Takrouri K, Chen T, Papadopoulos E, Sahoo R, Kabha E, Chen H, Cantel S, Wagner G, Halperin JA, Aktas BH, Chorev M. Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors. Eur J Med Chem 2014; 77:361-77. PubMed
  • Yefidoff-Freedman R, Chen T, Sahoo R, Chen L, Wagner G, Halperin JA, Aktas BH, Chorev M. 3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction. Chembiochem 2014; 15:595-611. PubMed
  • Denoyelle S, Chen T, Yang H, Chen L, Zhang Y, Halperin JA, Aktas BH, Chorev M. Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors. Eur J Med Chem 2013; 69:537-53. PubMed
  • Aktas BH, Qiao Y, Ozdelen E, Schubert R, Sevinc S, Harbinski F, Grubissich L, Singer S, Halperin JA. Small-Molecule targeting of translation initiation for cancer therapy. 2013; 4:1606-17. PubMed
  • Chen L, Aktas BH, Wang Y, He X, Sahoo R, Zhang N, Denoyelle S, Kabha E, Yang H, Freedman RY, Supko JG, Chorev M, Wagner G, Halperin JA. Tumor suppression by small molecule inhibitors of translation initiation. 2012; 3:869-81. PubMed
  • Hu W, Ge X, You T, Xu T, Zhang J, Wu G, Peng Z, Chorev M, Aktas BH, Halperin JA, Brown JR, Qin X. Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis. Cancer Res 2011; 71:2298-307. PubMed
  • Wu G, Chen T, Shahsafaei A, Hu W, Bronson RT, Shi GP, Halperin JA, Aktas H, Qin X. Complement Regulator CD59 Protects Against Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice. Circulation 2010; 121:1338-46. PubMed
  • Hu W, Yu Q, Hu N, Byrd D, Amet T, Shikuma C, Shiramizu B, Halperin JA, Qin X. A high-affinity inhibitor of human CD59 enhances complement-mediated virolysis of HIV-1: implications for treatment of HIV-1/AIDS. J Immunol 2009; 184:359-68. PubMed
  • Qin X,Hu W,Song W,Blair P,Wu G,Hu X,Song Y,Bauer S,Feelisch M,Leopold JA,Loscalzo J,Halperin JA. Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice. Am J Hematol 2009; 84:221-7. PubMed
  • Wu G,Hu W,Shahsafaei A,Song W,Dobarro M,Sukhova GK,Bronson RR,Shi GP,Rother RP,Halperin JA,Qin X. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res 2009; 104:550-8. PubMed
  • Qin X,Hu W,Song W,Grubissich L,Hu X,Wu G,Ferris S,Dobarro M,Halperin JA. Generation and phenotyping of mCd59a and mCd59b double-knockout mice. Am J Hematol 2008; 84:65-70. PubMed
  • Carganico S,Rovero P,Halperin JA,Papini AM,Chorev M. Building blocks for the synthesis of post-translationally modified glycated peptides and proteins. J Pept Sci 2008; 15:67-71. PubMed
  • Cantel S,Halperin JA,Chorev M,Scrima M,D'Ursi AM,Levy JJ,DiMarchi RD,Le Chevalier A,Rovero P,Papini AM. Side chain-to-side chain cyclization by intramolecular click reaction--building blocks, solid phase synthesis and conformational characterization. Adv Exp Med Biol 2009; 611:175-6. PubMed
  • Cantel S,Isaad Ale C,Scrima M,Levy JJ,DiMarchi RD,Rovero P,Halperin JA,D'Ursi AM,Papini AM,Chorev M. Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition. J Org Chem 2008; 73:5663-74. PubMed
  • Hu W, Ferris SP, Tweten RK, Wu G, Radaeva S, Gao B, Bronson RT, Halperin JA, Qin X. Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nat Med 2007; 14:98-103. PubMed
  • Hyberts SG, Heffron GJ, Tarragona NG, Solanky K, Edmonds KA, Luithardt H, Fejzo J, Chorev M, Aktas H, Colson K, Falchuk KH, Halperin JA, Wagner G. Ultrahigh-resolution (1)H-(13)C HSQC spectra of metabolite mixtures using nonlinear sampling and forward maximum entropy reconstruction. J Am Chem Soc 2007; 129:5108-16. PubMed
  • Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128:257-67. PubMed