# Development of small molecules to target KDM4B

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $410,606

## Abstract

ABSTRACT
 Epigenetic modifications of histone proteins play key roles in regulating transcription, and dysregulation
of the epigenetic machinery has emerged as important driver of cancer initiation and progression. Histone
lysine methylation is an important epigenetic mark that is dynamically regulated by histone methyltransferase
`writers' and histone lysine demethylase `erasers' (KDMs). The KDMs comprise two structurally and
mechanistically distinct classes of enzymes, and there is firm evidence that KDM4B in the larger Jumonji C
(JmjC) class has a particularly key role in several cancers including breast and prostate cancer, acute myeloid
leukemia and neuroblastoma. Published and ongoing studies from our group support the importance of
KDM4B in breast cancer and neuroblastoma. These results have prompted us to initiate screening, cell
biology and structural biology efforts to identify specific inhibitors of KDM4B. Two key findings from our studies
provide a proof-of-concept that targeting KDM4B is a potentially valuable therapeutic option in cancer
treatment. First, N-Myc recruits KDM4B to maintain low levels of repressive H3K9me2/me3 at Myc-binding
sites and promotes neuroblastoma growth. Second, the small molecule ciclopirox inhibits KDM4B activity,
suppresses the N-Myc pathway and reduces neuroblastoma growth.
 The immediate goal of this proposal within the scope of this FOA is to develop novel and potent
inhibitors of KDM4B that display specificity within the JmjC class of KDMs. Such inhibitors can then be used to
develop competent in vivo chemical probes to study the roles of KDM4B and other members of the KDM family
in relevant preclinical cancer models. A longer term goal is to develop small molecule cancer therapies that
target KDM4B. Previous biochemical and structural biology studies have thoroughly characterized the catalytic
mechanism and substrate specificities of these enzymes, and this information will fully exploited as we
proceed. Four laboratories with diverse expertise have and will continue to collaborate on this project: Drs. Jun
Yang and Andrew Davidoff (hit validation), Dr. Taosheng Chen (screening), and Dr. Stephen White
(biophysical studies and structural biology). In addition, Dr. Zoran Rankovic will provide medicinal chemistry
expertise that will be increasingly important as we move towards therapeutic development. As defined within
the FOA, the project includes 3 stages: assay development (Stage 1), primary screen implementation (Stage
2) and hit validation (Stage 3). Stages 1 and 2 are well advanced and the emphasis will therefore be on Stage
3.

## Key facts

- **NIH application ID:** 9954069
- **Project number:** 5R01CA229739-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Taosheng Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,606
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954069

## Citation

> US National Institutes of Health, RePORTER application 9954069, Development of small molecules to target KDM4B (5R01CA229739-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9954069. Licensed CC0.

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