# HTS for discovery of inhibitors of the centrosome-independent mitotic spindle machinery

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $370,575

## Abstract

Cancers are the leading cause of death for men and women in the USA between the ages of 40 and 79, with
lung cancer causing the most mortality. However, forty-five years after the National Cancer Act of 1971 (war on
cancer) was signed, progress in treating and curing cancer has been less than satisfying. Most anti-cancer
therapies have debilitating toxic effects on normal tissues that eventually limit treatment. Even for the most
cancer-selective therapeutics, cancers readily become drug resistant. The underlying molecular determinants
that allow, drive and support cancer are quite variable, poorly understood and only recently have been used to
design anti-cancer drugs. Thus, there is a significant need for improved therapeutics for cancer, including lung
cancer, that exploit vulnerabilities linked to the underlying molecular basis of that particular disease. Normal
cells, lacking the vulnerability, should be resistant to the cancer therapy. As an approach to identify
vulnerabilities in cancer not be shared by healthy cells, we conducted a genome-wide siRNA screen of a non-
small cell lung cancer (NSCLC) cell line and identified genes that were essential in this cell line, but not
essential in normal cells (Tagal et al., 2017). The cell line screened, NCI-H1819, lacked expression of
SMARCA4, a defect that is relatively common in several types of cancer. SMARCA4 encodes the protein Brg1,
a catalytic subunit of the chromatin remodeling SWI/SNF complex, an important regulator of transcription.
Through analysis of genes essential to NCI-H1819, but not normal cells, we identified a vulnerability to
inhibitors of Aurora kinase A, an important mitotic kinase. The basis of the defect was an impaired centrosome-
dependent mitotic spindle machinery. NSCLC cell lines that lacked Brg1 upregulate DLGAP5, which encodes
the protein HURP, an essential component of a centrosome-independent machinery for mitotic spindle
formation. siRNA targeting DLGAP5 was lethal for such cells, although expression of HURP is non-essential
for normal somatic cells, for which the centrosome-dependent pathway of spindle formation is present. Thus,
the complex containing HURP would be an ideal target for a therapeutic agent to treat cancers that have the
dual biomarkers, lack of expression of Brg1 and upregulation of HURP. This application is to conduct a high-
throughput screen of 300,000 drug-like chemicals to identify those that inhibit the centrosome-independent
mitotic machinery, kill Brg1 null, HURP positive cancers and are non-toxic for normal somatic cells.
In addition to providing potential leads for therapeutic approaches to cancer, specific chemical probes for
cellular mechanisms required for cancer cell growth also provide important research tools for understanding
basic cell biology or pathobiology. In the case of this application, the chemical probes generated will be
important tools for understanding the molecular machinery that regulates formation of the mitotic spin...

## Key facts

- **NIH application ID:** 9830038
- **Project number:** 5R01CA221978-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** MICHAEL G ROTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2017-12-14 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830038

## Citation

> US National Institutes of Health, RePORTER application 9830038, HTS for discovery of inhibitors of the centrosome-independent mitotic spindle machinery (5R01CA221978-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9830038. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*