# First-in-class ETS inhibitor TK216: Translational Biology and Oral Dosage Form Development

> **NIH NIH R44** · ONCTERNAL THERAPEUTICS, INC. · 2022 · $1,023,231

## Abstract

TK216 is an investigational, potentially first-in-class, targeted small molecule that is designed to specifically
inhibit the biological activity of the ETS family of oncoproteins. Tumorigenic gene fusions involving ETS factors
are frequently found in tumors, such as Ewing sarcoma (ES) as well as childhood leukemias and prostate
cancer. ETS factors are also often overexpressed in other tumors, such as neuroblastoma, lymphomas, acute
myeloid leukemia and high-grade glioma brain tumors. Based on work in the laboratory of our collaborator
Jeffrey Toretsky (Georgetown University), Oncternal Therapeutics, Inc. created the novel ETS family inhibitor
TK216. In preclinical models, TK216 inhibits the interaction between ETS family members and RNA helicase
A (RHA) leading to transcriptional changes and apoptosis. Oncternal is currently enrolling patients with
relapsed or refractory ES, a rare pediatric cancer that has historically been very challenging to treat effectively,
in a Phase 1 clinical trial. Interim analysis has shown TK216 to be generally well-tolerated, with dose limiting
toxicity of manageable myelosuppression and no obvious off-target toxicity. Notably, the current dosing
regimen demonstrated early exciting evidence of activity in seven evaluable patients with 1 surgical complete
response (CR) and 1 very good partial response (PR; 90% tumor shrinkage). TK216 has received Orphan
Drug and Fast Track Designations from the U.S. Food and Drug Administration (FDA) for treatment of
relapsed/refractory ES. ES is driven by an EWS-ETS fusion protein, which occurs through a reciprocal
chromosomal translocation. The EWS-ETS fusion protein was considered ‘undruggable’. However, the
mechanism of EWS-FLI1 is driven by its partnering with other proteins, thus TK216, similar to YK-4-279,
targets the EWS-ETS by disrupting or preventing protein-protein interactions (PPI). Given the significant need
for an EWS-ETS targeted therapy, the clinical development is being accelerated by administering TK216 as
a continuous infusion via ambulatory pump over 14 days. This allowed relapsed ES patients to gain access
and provide proof of efficacy. While this current form of administration is acceptable to patients suffering from
cancers with few or no other treatment options available, it poses a significant inconvenience hurdle for ES
patients as well as effectively prevents its clinical application in other unmet medical needs driven by ETS-
dysregulation. Therefore, we propose 2 main objectives for our proposal to support the TK216-based
therapies: a) delineation of the activity spectrum of TK216 against members of the ETS transcription factor
family and b) development an oral dosing form of TK216, including GLP pharmacology/toxicology studies and
GMP manufacturing. Our intent regarding ES is to offer a more convenient dosing form for ES patients and
to allow for expansion of TK216 studies into other oncology indications. The overarching goal of this project
is to compl...

## Key facts

- **NIH application ID:** 10473797
- **Project number:** 5R44CA261557-02
- **Recipient organization:** ONCTERNAL THERAPEUTICS, INC.
- **Principal Investigator:** Rajesh Krishnan
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,023,231
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473797

## Citation

> US National Institutes of Health, RePORTER application 10473797, First-in-class ETS inhibitor TK216: Translational Biology and Oral Dosage Form Development (5R44CA261557-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10473797. Licensed CC0.

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