# Targeted Chemical-Genetic Screen Platform for Identifying Novel AML Therapeutics

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2021 · $48,591

## Abstract

PROJECT ABSTRACT
Over 93% of cancer patients do not receive therapeutic benefit from oncology precision medicine. This can be
partly attributed to 1) not understanding the genetic targets and modes-of-action of putative targeted therapies,
and 2) lack of a well-characterized comprehensive drug compound library. To address these challenges, a shift
in the drug discovery paradigm from “target-centric” to “chemical-centric” approaches is necessary.
One such approach is chemical genomics, which involves screening drug compounds against a collection of
defined gene mutants to identify mutations that sensitize or suppress a drug’s effect. These chemical-genetic
interactions can be quantified by measuring mutants’ cell viability in the presence of compounds of interest.
The entire set of mutant viability measurements for a given compound, called a “profile”, can then be used as a
“fingerprint” to understand a drug’s modes-of-action. These screens can be performed in human cell lines
using a pooled lentiviral CRISPR-Cas9 approach. While current genome-wide screens (~70,000 sgRNAs
targeting ~18,000 genes) can inform candidate chemical compounds for drug development, many labs do not
have the resources to perform these large-scale screens for more than a small number of compounds. Recent
preliminary data from our labs show that screens with a small targeted CRISPR library (~3,000 sgRNAs
targeting ~1,000 genes) can 1) recover similar biological information in a compressed library compared to
genome-wide screens, and 2) reduce resource costs to allow for higher-throughput drug screening.
TP53-mutant acute myeloid leukemia (AML) patients currently have very poor prognosis (1-2 year survival
rates of 0-10%). There are currently no effective therapeutics for this patient subpopulation. However, a recent
study showed that a TP53 KO AML cell line showed increased sensitivity to a panel of small-molecule
inhibitors. The targeted chemical-genetic screen approach we develop here can reveal the genetic targets of
these putative drugs to help with prioritizing lead compounds for drug development.
The overall goal of this proposal is to develop a targeted CRISPR-Cas9 chemical-genetic screen approach and
to develop a computational method to predict drug mode-of-action from chemical-genetic interaction data. I will
pursue the following aims: (1a) develop and validate targeted screens in human cell lines, (1b) develop a
computational method to score chemical-genetic interactions, rank candidate drug targets, and predict drug
mode-of-action, and (2) elucidate mechanism-of-action of putative drug inhibitors for TP53-mutant AML using
this targeted chemical-genetic screen approach. Completion of this study will result in a method for efficient
discovery of drug mode-of-action and has implications for better understanding of how cancer (AML)
therapeutics work. This work will also advance my understanding of computational tool development and
application in clinical oncology, a...

## Key facts

- **NIH application ID:** 10140623
- **Project number:** 1F30CA257227-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Kevin Jeng-Yen Lin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,591
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140623

## Citation

> US National Institutes of Health, RePORTER application 10140623, Targeted Chemical-Genetic Screen Platform for Identifying Novel AML Therapeutics (1F30CA257227-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140623. Licensed CC0.

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