# Diversity Supplement: Cheminformatics-based identification of leukemia-targeting molecules

> **NIH NIH R21** · RICE UNIVERSITY · 2024 · $45,931

## Abstract

Contact PD/PI: Kirienko, Natasha V
SUMMARY
Acute myeloid leukemia (AML) is the most common acute leukemia in the US, with ~20,000 new diagnoses
and ~11,000 deaths per year. This pernicious hematological malignancy has rapid progression and startling
mortality in untreated patients. This is particularly true for elderly patients (i.e., > 65 years of age), where up to
70% of newly diagnosed patients succumb within a year. These patients have worse prognoses, often cannot
tolerate the most aggressive (and effective) treatment courses, are less likely to obtain complete remission af-
ter standard induction and consolidation treatment, and are more likely to have serious complications and side
effects. Using bioinformatic and bench approaches, we found the leukemic cells show striking sensitivity to mi-
tochondrial toxins. Our subsequent research identified a correlation between lower coupling efficiency in the
mitochondria of AML cells and increased sensitivity to mitochondrial damage. We showed strong synergy be-
tween multiple combinations of mitochondria-targeting molecules and known anti-cancer agents in AML, but
not healthy cells, selectively killing cancer cells. We hypothesized that hematological cancers accrue substan-
tial mitochondrial damage but reduce activation of mitochondrial recycling (mitophagy), likely in an effort to
maintain their cell division potential. However, over-activating mitophagy causes a crisis that triggers pro-
grammed cell death pathways. To leverage these findings, we performed a high-throughput screen and identi-
fied 8 compounds that increased levels of mitophagic activator kinase PINK1, driving mitochondrial turnover.
Iterative structure-activity relationship studies yielded two analogs, named PS127B and PS127E, with CC50AML
in the nM range; healthy cells survived the drug at up to 20 times these concentrations. These molecules inhib-
it mitochondrial function, reduce oxygen consumption and ATP production, and activate several programmed
cell death pathways. These compounds also synergized with known AML chemotherapeutics, were effective
against primary AML cells (including leukemia stem cells), and reduced tumor burden and extended survival
in mice engrafted with human leukemia cells. A subsequent in silico screen of over 4 M compounds using two
predicted activities (apoptotic agonist and thioredoxin glutathione reductase inhibition) shared by multiple cyto-
toxic PS127-family members (but missing for non-cytotoxic members) identified 213 hits. 93 of these hits were
in a cluster of compounds with chemical similarity to the PS127 family. 23 others were in a second group,
structurally related to each other, but not to PS127. In this project, we will validate cheminformatics predictions
of these comounds’ molecular targets, determine their effects on cellular metabolism, and confirm that they
trigger mitophagic activation via the PINK1/Parkin axis in mammalian cells. Completion of the proposed exper-
iments will id...

## Key facts

- **NIH application ID:** 11062159
- **Project number:** 3R21CA280500-01A1S1
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** Natasha Kirienko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,931
- **Award type:** 3
- **Project period:** 2024-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062159

## Citation

> US National Institutes of Health, RePORTER application 11062159, Diversity Supplement: Cheminformatics-based identification of leukemia-targeting molecules (3R21CA280500-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11062159. Licensed CC0.

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