# Development of selective HDAC6 inhibitors to improve cancer immunotherapy

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2022 · $514,297

## Abstract

Project Summary
 The median survival for metastatic melanoma is approximately 8–16 months, and few therapies offer a
significant improvement in overall survival. However, immunotherapeutic strategies that abrogate immunologic
checkpoints or improve immunosurveillance have shown promise, especially in melanoma.
 We have found that both genetic abrogation and pharmacologic inhibition of HDAC6 leads to a
decreased infiltration of pro-tumoral tumor-associated macrophages and downregulation of
immunosuppressive mediators. These effects translated into a pronounced delay of in vivo melanoma tumor
growth, which is, at least in part, dependent on intact immunity, as evidenced by the restoration of tumor
growth after CD4+ and CD8+ depletion. Our findings demonstrate a significant immunoregulatory role of
HDAC6 in melanoma, providing a rationale for the use of selective HDAC6is to improve antitumor immunity.
We are most interested in identifying HDAC6is that are best able to reduce the pro-tumoral phenotype of
tumor-associated macrophages and decrease the expression of immunosuppressive surface molecules such
as PD-L1 and PD-L2 while showing little cytotoxicity on their own.
 Our goal is thus to design, synthesize, and test new HDAC6i both in vitro and in vivo for use in the
treatment of melanoma and other malignancies. The aims to be accomplished under this grant are as follows:
1. Using molecular modeling, design, and synthesize ~50 new HDAC6is per year, for the first three years and
test these for HDAC isozyme selectivity; the last two years of the grant will focus on compound scale-up,
preclinical translational studies, and advanced ADMET testing.
2. Evaluate compounds that have IC50 values of <50nM and at least 400-fold HDAC6 selectivity using in vitro
melanoma models to measure acetylated tubulin, pSTAT3, PD-L1 levels, and cytotoxicity. For compounds
found to decrease levels of pSTAT3 and PD-L1, while increasing acetylated tubulin, conduct early-stage
ADMET studies (2 – 3/year) using a CRO, and if needed, modify the compounds using principles of medicinal
chemistry and molecular modeling based methods to increase the compound’s drug-like character.
3. Lastly, test the best compounds for their ability to delay tumor growth in syngeneic murine melanoma
models, both as stand-alone and in combination with PD-1 blocking antibodies. Additionally, we will evaluate
our best candidates using humanized PDX models and as a cell therapy pre-treating macrophages to avoid
their switch to M2-like protumoral phenotype. Those candidates showing the best in vivo efficacy will be sent
for advanced ADMET, including chronic toxicity studies, cardiac activity, and pulmonary activity in rats.
 Our proposed work is significant as it helps to fill this critical knowledge gap and thus moves epigenetic-
based combination immunotherapies to a new level. The concept to be validated is novel as it significantly
deviates from the classical cytotoxic role of HDAC inhibitors as anti...

## Key facts

- **NIH application ID:** 10706017
- **Project number:** 7R01CA249248-03
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Cyril Barinka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $514,297
- **Award type:** 7
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706017

## Citation

> US National Institutes of Health, RePORTER application 10706017, Development of selective HDAC6 inhibitors to improve cancer immunotherapy (7R01CA249248-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10706017. Licensed CC0.

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