Small Molecule Inhibitors of Drug Resistant Forms of HIV-1 Integrase

Integrase strand transfer inhibitors (“INSTIs”) are currently in use as a component of prophylactic antiretroviral therapy for preventing HIV-1 infection from progressing to AIDS. Three INSTIs are approved by the FDA for inclusion in antiretroviral regiments: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). Clinicians have already identified several HIV-1 integrase mutations that confer resistance to RAL and EVG, and additional mutations that confer resistance to all three INSTIs has been identified in the laboratory.

Researchers at the National Cancer Institute discovered small-molecule compounds containing 1-hydroxy-2-oxo-1,8-naphthyridine moieties whose activity against HIV-1 integrase mutants confer resistance to currently approved INSTIs. These new compounds exhibit potent and selective activity against comprehensive and varied panels of INSTI-resistant mutants of HIV-1 integrase. Preliminary rodent efficacy, metabolic, and pharmacokinetic studies have been completed by the NCI researchers.

The National Cancer Institute (NCI) seeks partners to in-license or co-develop this class of compounds for therapeutic use. Parties interested in licensing the technology should submit an Application for Licensing, and seek detailed information from the Licensing and Patenting Manager indicated below.

Co-development partners would apply under a Cooperative Research and Development (CRADA) to conduct pre-clinical studies that include lead optimization, in vitro and in vivo evaluation and preclinical development of a novel series of INSTIs for the treatment of infection by HIV-1 strains with resistance to currently available integrase inhibitors, including raltegravir and elvitegravir. Under the CRADA, further in vitro and in vivo ADME, as well as activity studies, will be conducted by the partner on current and optimized lead compounds using rodent and non-rodent models.   Efficacy studies in non-human primates of select compounds are needed and will be part of the CRADA program.  The CRADA scope will also include all aspects of toxicity studies, and synthesis scale up under GMP of optimized lead compounds to support submission of a successful IND application.

Interested potential CRADA collaborators can receive detailed information by contacting the Licensing and Patenting Manager (see below). Interested parties will receive detailed information on the current status of the project after signing a confidentiality disclosure agreement (CDA) with NCI.  Interested candidate partners must submit a statement of interest and capability to the NCI point of contact for consideration by 5:00pm Eastern Standard Time, December 30, 2016.

Guidelines for the preparation of a full CRADA proposal will be communicated to all respondents with whom initial confidential discussions have been established. Licensing of background technology related to this CRADA opportunity is also available to potential collaborators. All proposals received by the above date will be considered.  NCI reserves the right to consider additional proposals or none at all if no partner is selected from the initial response.

Potential Commercial Applications: Competitive Advantages:
  • HIV therapeutic for drug-resistant compounds of HIV-1 integrase
  • Currently, the only INSTI effective against drug resistant mutants of HIV-1 integrase

Development Stage:
Pre-clinical (in vivo)


Terrence Burke (NCI)  ➽ more inventions...

Stephen Hughes (NCI)  ➽ more inventions...

Yves Pommier (NCI)  ➽ more inventions...

Xue Zhao (NCI)  ➽ more inventions...

Mathieu Metifiot (NCI)  ➽ more inventions...

Stephen Smith (NCI)  ➽ more inventions...

Barry Johnson (NCI)  ➽ more inventions...

Christophe Marchand (NCI)  ➽ more inventions...

Intellectual Property:
U.S. Pat: 9,676,771 issued 2016-06-13
US Provisional Application No. 61/899,061
US Non-Provisional Application No. 14/891,309

Zhao X, et al. HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases. PMID: 26808478
Métifiot M, et al. Selectivity for strand-transfer over 3'-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme-DNA interactions in the active site. PMID: 27369381
Zhao X, et al. 4-amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against raltegravir-resistant integrase mutants of HIV-1. PMID: 24901667
Zhao X, et al. Inhibiting the HIV Integration Process: Past, Present, and the Future. PMID: 24025027

Collaboration Opportunity:

Licensing and research collaboration

Licensing Contact:
John Hewes, Ph.D.
Phone: 240-276-5515

OTT Reference No: E-093-2013
Updated: Dec 23, 2020