# SIRT2 Inhibitors for the Treatment of B-cell Lymphoma

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $467,882

## Abstract

We propose to develop inhibitors of NAD+-dependent deacetylase SIRT2 as new, targeted, non-toxic
chemotherapeutic agents that inactivate BCL6, a key driver of tumorigenesis in B-cell lymphoma. Common
genetic drivers for germinal center B cell-derived lymphomas have be identified through large scale
sequencing efforts. However, transferring this knowledge into novel therapies remains challenging, particularly
for loss-of-function mutations where the driver is absent and a valid therapeutic target is not immediately
obvious. Up to 40% of germinal center-derived lymphomas, including both aggressive, diffuse large B-cell
lymphoma (DLBCL), and indolent, follicular cell lymphoma (FL), contain loss of function mutations in histone
acetyl transferases (HATs), CREBBP and p300, making loss-of-function mutations in HATs among the most
common genetic alterations in lymphoma. Therapies aimed at these genetic alterations may therefore help
large fraction of lymphoma patients.
While loss of function mutations in HATs can be found at low frequency in other cancers, their extraordinarily
high prevalence in DLBCL and FL suggests a fundamental role of dysregulated acetylation in the pathogenesis
of germinal center-derived malignancies. Reduced activity of cellular HATs has been implicated in
dysregulation of two critical mediators of lymphomagenesis, BCL6 and p53, which are rendered hyperactive
and hypoactive, respectively, by the hypoacetylated state. We show that pharmacological inhibition SIRT2
counteracts the protein acetylation imbalance that drives lymphomagenesis, and thus constitutes a novel
therapeutic strategy for treatment of germinal center-derived lymphomas. Our preliminary data validate this
therapeutic strategy and provide evidence that BCL6 inactivation through SIRT2 inhibition consititues the basis
for the anti-lymphoma activity. Based on this rationale and our preliminary data, we propose to: optimize SIRT2
inhibitors using medicinal chemistry and structure-based drug design; identify the mechanisms by which SIRT2
inhibitors abrogates BCL6 function, and; demonstrate in vivo anti-lymphoma activity. As a result, we will
provide a novel therapeutic strategy and develop small molecule SIRT2 inhibitors, targeting one of the most
common genetic alterations in germinal center-derived malignancies.

## Key facts

- **NIH application ID:** 9947892
- **Project number:** 5R01CA206462-05
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Antonio Bedalov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,882
- **Award type:** 5
- **Project period:** 2016-07-07 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9947892

## Citation

> US National Institutes of Health, RePORTER application 9947892, SIRT2 Inhibitors for the Treatment of B-cell Lymphoma (5R01CA206462-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9947892. Licensed CC0.

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