Faculty Directory

Hovhannes Gukasyan

Hovhannes Gukasyan

Associate Professor of Pharmacology and Pharmaceutical Sciences (Teaching Track)

Department of Pharmacology and Pharmaceutical Sciences

Hovhannes (Hovik) Gukasyan, PhD, is an associate professor of pharmacology and pharmaceutical sciences, and is helping grow the school’s undergraduate major in biopharmaceutical sciences. He spent two decades in the pharmaceutical industry, including roles at Pfizer and AbbVie, and served as an adjunct professor at the USC School of Pharmacy and Keck Graduate Institute School of Pharmacy and Health Sciences. He earned a PhD in pharmaceutical sciences from the USC School of Pharmacy.

Areas of Expertise

  • Drug Discovery
  • Ocular Pharmacology
  • Biophysics
  • Molecular Drug Delivery
  • Nanotechnology
  • Regulatory Science
  • Education

    USC School of Pharmacy

    PhD

    University of Southern California

    BS

  • Selected Articles

    Design and Characterization of a Pyridone-Containing EZH2 Inhibitor Phosphate Prodrug

    Journal of Medicinal Chemistry

    A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor’s aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.

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    Ocular biopharmaceutics: impact of modeling and simulation on topical ophthalmic formulation development

    Elsevier Current Trends

    The estimation of ocular pharmacokinetics (PK) in various eye tissues is limited because of sampling challenges. Computational modeling and simulation (M&S) tools underpinning the elucidation of drug access routes and prediction of ocular exposure are essential for the mechanistic assessment of biopharmaceutics in the eye. Therefore, theoretical and experimental evaluation of ocular absorption and transit models is necessary. Biopharmaceutical parameter sensitivity analysis based on permeability and drug dose illustrates utility in ocular drug delivery assessment, which could have innovative and cost-saving impacts on ophthalmic product development and therapeutic bioequivalence (BE) evaluations.

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    Safety Assessment of Formulation Vehicles Following Intravitreal Administration in Rabbits

    Ophthalmic Drug Discovery and Development

    Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety. Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment.

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    Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies

    Journal of Medicinal Chemistry

    A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group.

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    Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

    Journal of Medicinal Chemistry

    A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

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    PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

    Cancer Cell

    We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

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  • Affiliations
    • American Chemical Society

    • Association for Research in Vision and Opthalmology

    • American Association of Pharmaceutical Sciences

    • Controlled Release of Society

    • American Association for Cancer Research

  • Accomplishments

    Pfizer Worldwide Research and Development W.E. Upjohn Prizes Award

    Pfizer Worldwide Research and Development W.E. Upjohn Prizes Award for KGI School of Pharmacy 2-week Experiential Training course on site in La Jolla.