# Aminonaphthyridine compounds as potential therapeutics for lung and thyroid cancers

> **NIH NIH R41** · KINARX, LLC · 2020 · $399,933

## 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 >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.

## Key facts

- **NIH application ID:** 10008053
- **Project number:** 1R41CA250707-01
- **Recipient organization:** KINARX, LLC
- **Principal Investigator:** Frederick Wayne Holtsberg
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,933
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10008053

## Citation

> US National Institutes of Health, RePORTER application 10008053, Aminonaphthyridine compounds as potential therapeutics for lung and thyroid cancers (1R41CA250707-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10008053. Licensed CC0.

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