Ruben Abagyan
· Ph.D.VerifiedUniversity of California, San Diego · Pharmaceutical Sciences
Active 1984–2026
About
Ruben Abagyan, PhD, is a professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences. His research focuses on the development of novel technologies for structure-based drug discovery and optimization, structural systems biology for target finding, and protein modeling. His laboratory screens specific biomedical targets to discover new drug leads and validate them experimentally, with applications spanning cancer, neurodegeneration, parasitic, viral, and endocrine diseases. He models alternative functional states and allosteric pockets of kinases, GPCRs, and Nuclear Receptors, and has derived comprehensive sets of ligand pockets, known as the Pocketome, for target identification and multi-target pharmacology profiling. His work includes docking drugs, leads, and environmental chemicals to models predicting endocrine disruption and adverse effects, as well as identifying new uses for existing drugs based on multi-target pharmacology. Dr. Abagyan has made significant contributions to the fields of internal coordinate mechanics for structure sampling, dynamics, molecular docking, and structure-based lead discovery, establishing himself as a leading figure in computational drug discovery.
Research topics
- Biology
- Botany
- Biochemistry
Selected publications
Journal of Medicinal Chemistry · 2026-04-29
articleOpen accessdisplayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
Cancer Research · 2026-04-03
articleSenior authorAbstract PTPN2 inhibition is a novel immuno-oncology approach: by releasing an intracellular “brake” it increases cytokine responsiveness (e.g., IFN-γ/JAK-STAT), boosts antigen presentation, and enhances T-cell cytotoxicity, helping to overcome immune evasion in tumors resistant to PD-1 blockade.Our development candidate ZE00-0388 demonstrates potential best-in-class profile: Nanomolar potency with high selectivity for PTPN2/1 over other phosphatases, predictable PK/PD with sustained exposure above EC50, and proven target engagement. ZE00-0388 shows favorable bioavailability in all species, with best translation expected from dog to human.The combination of anti-mPD-1 and ZE00-0388 exhibited remarkable dose-dependent anti-tumor efficacy against the subcutaneous MC38 colon model. Solo treatments with ZE00-0388 demonstrated tumor growth inhibition of 81% and in combination with anti-mPD-1 complete regression of tumor in 50% of animals. ZE00-0388 has a very favorable safety profile with tolerated doses significantly above pre-clinical proof-of-concept efficacious doses, which indicates that ZE00-0388 should have a very broad therapeutic window. Citation Format: Alexei Pushechnikov, Ruben Karapetian, Stepan Mochalov, Sanja Baumann Tomovska, Nikolay Savchuk, Iain Dukes, Ruben Abagyan. Efficacy, in vivo safety, and PK/PD studies for novel, oral, highly selective PTPN2/1 inhibitor (ZE00-0388) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7926.
Figshare · 2026-04-29
articleOpen accessAccumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer’s disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (<b>1</b>). Modification of the thieno[3,2-<i>d</i>]pyrimidine central core of <b>1</b> led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (<b>27</b>, <b>28</b> (ARN25699) and <b>31</b> (ARN26646)). Among these, <b>28</b> displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
Figshare · 2026-04-29
datasetOpen accessAccumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer’s disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (<b>1</b>). Modification of the thieno[3,2-<i>d</i>]pyrimidine central core of <b>1</b> led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (<b>27</b>, <b>28</b> (ARN25699) and <b>31</b> (ARN26646)). Among these, <b>28</b> displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
Figshare · 2026-04-29
datasetOpen accessAccumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer’s disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (<b>1</b>). Modification of the thieno[3,2-<i>d</i>]pyrimidine central core of <b>1</b> led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (<b>27</b>, <b>28</b> (ARN25699) and <b>31</b> (ARN26646)). Among these, <b>28</b> displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
Figshare · 2026-04-29
datasetOpen accessAccumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer’s disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (<b>1</b>). Modification of the thieno[3,2-<i>d</i>]pyrimidine central core of <b>1</b> led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (<b>27</b>, <b>28</b> (ARN25699) and <b>31</b> (ARN26646)). Among these, <b>28</b> displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
Figshare · 2026-04-29
datasetOpen accessAccumulation of microtubule-associated protein tau is a neurotoxic hallmark in Alzheimer’s disease (AD) and related tauopathies. To date, no small molecule disease-modifying therapy exists, underscoring an urgent unmet need. In this context, the multitarget-directed ligand (MTDL) approach offers a viable polypharmacological option for modulating key pathways/targets involved in tau pathology. Leveraging the interconnected roles of GSK-3β, FYN, and DYRK1A in tau hyperphosphorylation, we conducted a computational and X-ray crystallography-driven SAR exploration around our previously disclosed GSK-3β/FYN/DYRK1A inhibitor ARN25068 (<b>1</b>). Modification of the thieno[3,2-<i>d</i>]pyrimidine central core of <b>1</b> led to the discovery of quite well-balanced GSK-3β/FYN/DYRK1A triple-targeting analogs (<b>27</b>, <b>28</b> (ARN25699) and <b>31</b> (ARN26646)). Among these, <b>28</b> displayed a favorable ADME profile, acceptable pharmacokinetic properties, and efficacy in an in vitro tau phosphorylation assay, outperforming three single-target inhibitors tested individually or in combination. These compounds represent promising MTDL leads poised to advance therapeutic innovation in AD and related tauopathies.
medRxiv · 2025-10-19
preprintOpen access1st authorCorrespondingABSTRACT Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have become widely used not only for glycemic control but also for their protective cardiovascular effects. However, concerns about adverse events including diabetic ketoacidosis and kidney damage, have gained attention, since these agents are used both as a monotherapy and in combination with metformin. In this study, we analyzed 170,000 adverse event reports submitted to the FDA Adverse Event Reporting System for diabetic ketoacidosis (DKA), kidney injury, and lethal outcomes. Reporting odds ratios (RORs) and 95% confidence intervals (CI) revealed substantial variation in adverse event profiles across the six treatments under study. Canagliflozin shows the highest numbers on kidney damage (14.6%) of all SGLT2i monotherapies. Combination with metformin reduces it slightly (14.3%), but results in significantly elevated ketoacidosis (from 15.4% to 22.3%). Empagliflozin adverse effect profile is different, the metformin combination does not change the reported risk of kidney damage, but dramatically increases ketoacidosis from 14.7% to 27.9%, the highest number of all SGLT2i’s and their combinations. Notably, the DKA risk of each the three combinations exceeded the same parameter for a corresponding SGLT2i monotherapy of metformin alone. Metformin alone, on the other, is not associated with ketoacidosis (<1.1%), but has a high reported risk of death (12.7%) and kidney damage (18.7%), while adding any SGLT2i to the regimen reduces this kidney damage level dramatically. These observations call for individualized risk-benefit assessment of a safe and effective antidiabetic treatment regimen, particularly in patients with ketoacidosis-related comorbidities.
Journal of Innovative Solutions for Eco-Environmental Sustainability · 2025-10-21
articleOpen accessSenior authorImmune checkpoint inhibitors (ICIs), including anti-PD-1, PD-L1, and CTLA-4 antibodies, have advanced cancer therapy but are often associated with serious immune-related adverse events (irAEs). Analysis of over 80,000 monotherapy reports from the FDA Adverse Event Reporting System revealed that co-occurring infections significantly increase irAE risk - including events such as sarcoidosis, pneumonitis, colitis, hepatitis, myocarditis, and nephritis. The presented work and our initial findings [1] highlights the critical need for improved therapeutic strategies. To overcome the limitations of antibody-based ICIs - such as therapeutic efficacy, high cost, limited tissue penetration, and immunogenicity and engage new mechanism of PD-L1 internalization - we performed an in silico screening to identify small-molecule PD-L1 “glue” like modulators. We used ICM-Pro software with GPU acceleration to screen 1.5 million compounds from the ChemBridge library. After that, we filtered the results based on their chemical properties. Next, we selected 20,000 compounds and performed redocking. Finally, we refined the top 200 compounds for further analysis. Final candidates were selected for in vitro testing. Two lead compounds are currently under experimental evaluation and being compared with BMS-202, a known PD-L1 small molecule inhibitor. This combined clinical and computational approach supports the development of next-generation, low-toxicity immunotherapies.
Cancer Research · 2025-04-21
articleSenior authorAbstract Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is ubiquitously expressed, primarily in hematopoietic and placental cells. Critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. Thus, enhancing IFNγ sensing and signaling through the inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer immunotherapy regimens. Historically, phosphatases are difficult drug targets; due to an intrinsic physicochemical profile of phosphatase inhibitors, finding bioavailable molecules is a great challenge. ZE00-0388 demonstrates sub-nanomolar PTPN2/N1 inhibitory activity and outstanding over 1000-fold selectivity against all other phosphatases. ZE00-0388 demonstrated complete tumor remission in combination with the anti-mPD-1 recombinant mAb therapy in the murine colon adenocarcinoma MC38 in vivo model. ZE00-0388 demonstrates good safety and tolerability; its ADME properties confirm that ZE00-0388 is suitable for further development for combination therapies. Citation Format: Alexei Pushechnikov, Vladislav Parchinsky, Aleksei Riakhovskii, Stepan Mochalov, Ruben Karapetian, Amy Burd, Nikolay Savchuk, Iain Dukes, Ruben Abagyan. Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule PTPN2/1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5607.
Recent grants
NIH · $9.1M · 2015
Addressing biomedical challenges with computational mechanics and big data
NIH · $1.9M · 2019–2024
NIH · $4.2M · 2020
NIH · $680k · 2002
NIH · $347k · 2010
Frequent coauthors
- 155 shared
Irina Kufareva
University of Montana
- 154 shared
Andrew Orry
Molsoft (United States)
- 141 shared
Polo C.‐H. Lam
Molsoft (United States)
- 127 shared
Laurence J. Miller
Mayo Clinic in Arizona
- 120 shared
Patrick M. Sexton
Australian Research Council
- 119 shared
Maxim Totrov
Molsoft (United States)
- 86 shared
Vsevolod Katritch
University of Southern California
- 86 shared
Arthur Christopoulos
Monash University
Awards & honors
- Two CapCure awards for excellence in prostate cancer researc…
- Princess Diana award and medal, Sydney (2003)
- UCSD Faculty and Staff Excellence Award (2007)
- AACP’s 2016 Teacher of the Year Award
- SSPPS Student-voted Faculty of the Year Award (2018)
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