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Aminonaphthyridine compounds as potential therapeutics for lung and thyroid cancers

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA250707-01
Agency Tracking Number: R41CA250707
Amount: $399,933.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA19-270
Timeline
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-06-01
Award End Date (Contract End Date): 2021-05-31
Small Business Information
4 RESEARCH CT STE 350
Rockville, MD 20850-3220
United States
DUNS: 081288833
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 FREDERICK HOLTSBERG
 (240) 778-6523
 rick@integratedbiotherapeutics.com
Business Contact
 FREDERICK HOLTSBERG
Phone: (240) 506-0603
Email: fholtsberg@kinarx.com
Research Institution
 PURDUE UNIVERSITY
 
155 S GRANT STREET
WEST LAFAYETTE, IN 47907-2114
United States

 Nonprofit College or University
Abstract

Over the past three decades a growing number of cancer-driving protein kinases have been successfully
targeted as reflected in the approval of 49 kinase inhibitors by the Food and Drug Administration (FDA). Recent
approval of the first tyrosine kinase inhibitor (Larotrectinib) for treatment of any cancer bearing mutation in
neurotrophic receptor kinase validated a novel paradigm of precision targeting of the molecular driver rather than
treatment based on cancer type defined by anatomic sites. The receptor tyrosin kinase (RTK) known as
rearranged during transfection (RET) is mutated or chromosomally rearranged in multiple malignancies including
2% of non-small cell lung cancers (NSCLC), 20–80% of sporadic medullary thyroid cancers (MTC) and andgt;95% of
patients with familial MTC and multiple endocrine neoplasia 2 (MEN2) leading to very poor prognosis for these
patients. Currently two RET inhibitors, cabozantinib and vandetanib, have been FDA approved for treatment of
MTC and none is approved for treatment of RET-driven NSCLC. These agents have poor activity towards
clinically important RET mutants including the gatekeeper mutations V804L/M. Two new, more potent RET-
specific drugs Loxo-292 and Blu-667 are in clinical development. Our recent findings have identified additional
RET mutants that are resistant to Loxo-292 and Blu-667. Given the evolution of mutational landscape upon
introduction of new inhibitors, a pipeline of novel and potent inhibitors is critical for meeting this challenge. We
have developed a novel chemical scaffold with potent activity against a wide range of clinically relevant RET
mutants. These compounds exhibit orders of magnitude superior activity compared to cabozantinib and
vandetanib, and potent activity towards mutants that are resistant to LOXO-292 and Blu667. The compounds
are orally bioavailable. The objective of this multiple PI (MPI) Phase I STTR is to complete the lead optimization
and selection of the final candidate for advanced development. In Aim 1, a set of up to 15 analogs will be
characterized for RET-specific inhibitory activity against a range of mutants and RET fusions. Preliminary safety
and bioavailability profile will be evaluated to exclude compounds with potential liabilities. Up to 4 lead
compounds will be then tested in Aim 2 for in vivo activity in xenograft models of RET-driven thyroid cancer, a
novel transgenic model of NSCLC driven by a RET fusion, as well as an allograft model of LOXO-292 and Blu-
667 resistant RET mutant. The expected final outcome of this Phase I STTR will be a lead and a back-up
candidate for further advanced development under a follow-on Phase II project.Project Narrative
A subset of non small cell lung cancer and medullary thyroid cancers contain genetic
alterations in a gene called RET that encodes for a specific enzyme. In this proposal we
develop a novel set of drug candidates that specifically inhibit this enzyme leading to
prevention of the growth of cancer cells. Therapeutic candidates will be selected based
on a set of safety and efficacy studies.

* Information listed above is at the time of submission. *

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