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NIH grant 1R56AI198710-01: Selective GAK inhibitors to combat dengue, Venezuelan equine encephalitis and other emerging viral infections
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Shirit Einav. Award: $720714.
Start: 2026-08-21T00:00:00.
Abstract
There is an urgent need for more effective antiviral development to address the unmet challenge posed by multiple emerging global viral threats, including dengue (DENV) and Venezuelan equine encephalitis (VEEV) viruses. Over the past decade, our laboratory has uncovered the critical role of cellular kinases in RNA virus trafficking and their potential as targets for broad-spectrum antivirals, demonstrating proof-of-concepts for the utility of host-targeted approaches against multiple emerging viruses. One such promising target is Cyclin GAssociated Kinase (GAK), a NUMB-associated kinase (NAK) that we have shown to regulate intraceullar trafficking of RNA viruses during both the entry and assembly/egress stages of their life cycle, establishing it as a “master regulator” of viral infection. Notably, the approved anticancer drugs sunitinib and erlotinib, which inhibit both GAK and AAK1 (another NAK), protect mice from DENV and Ebola virus (EBOV) with a high barrier to resistance. However, due to the narrow therapeutic index (TI) of this non-selective combination, we have developed novel, highly selective GAK inhibitors, including a new series of potent 4-anilinoquinoline-based compounds. Our data provide evidence that these compounds are safe and highly effective against DENV, VEEV, EBOV, and other viruses. Remarkably, CA93.0, the initial lead in this series, protects mice from a lethal DENV challenge, albeit requiring co-administration of a cytochrome P450 inhibitor. A focused SAR effort has yielded more stable, in vivo-safe analogs, including CA3-222, supporting the feasibility of the work. Building on our success in GAK structural biology, medicinal chemistry, and inhibitor design, we hypothesize that modifying the substitution pattern of lead molecules will yield potent, selective, and safe broad-spectrum antivirals with enhanced PK and ADME properties. Aim 1 will use a multi-dimensional medicinal chemistry approach to optimize the TI, PK profile, and blood-brain barrier permeability of CA3-222 analogs, while maintaining selectivity. These analogs will be tested for GAK activity and antiviral activity, followed by kinase selectivity analysis, in vitro ADMET studies, and PK profiling in mice. Computational and structural analyses of the GAK binding mode will refine the iterative lead optimization process and enhance its efficiency. Promising pre-IND candidates will be downselected via additional ADME-T testing, and dosing regimens defined. Aim 2 will assess the therapeutic potential of existing and newly synthesized GAK inhibitors, both as monotherapies and in combination drug regimens. Their effects on viral replication, cytokine response, and tissue injury will be evaluated using human primary cells, a validated gravity-flow neurovascular unit (gNVU) model, and mouse models of DENV and VEEV. Lastly, we will monitor target modulation and validate candidate egagement biomarkers. Successful completion of this study will deliver a novel, drug-like small molecule candidate to protect from DENV, VEEV, and multiple other emerging viruses along with preclinical datasets to support IND applications and guide clinical trial design.document fetched 2026-08-30 02:46