# Modulation of BAK in Lung Cancer Therapeutics

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $356,850

## Abstract

Most patients with lung cancer have a poor prognosis due to genetic alterations and resistance to conventional
therapy. The development of novel and more effective drugs is critical to improve the prognosis of patients with
both non-small cell lung cancer (NSCLC) and small lung cancer (SCLC).  BAK is a key multidomain
proapoptotic molecule in the Bcl2 family, which is required for apoptotic cell death.  Because BAK is normally
an integral outer mitochondrial membrane protein, whereas BAX requires translocation from the cytosol after
an apoptotic stimulus, BAK activation may be more tractable.  The formation of BAK homo- or heterodimers is
an important mechanism in the induction of apoptosis. Bcl-XL and Mcl-1 can bind to BAK, which is presumably
in a ‘primed’ conformation with its BH3 domain exposed, while in apoptosis-induced cells, a BH3-only protein
displaces BAK from the anti-apoptotic heterodimer. The free BAK then forms an oligomer that elicits the
permeabilization of the mitochondrial outer membrane and the release of cytochrome c leading to apoptosis.
The BH3 binding pocket is located between BAK α2 and β3, which is an ideal site for the design or screening
of BAK activators for the development of potential new anti-cancer agents. We chose the BH3 domain binding
pocket (aa75-90) of BAK as a docking site for the screening of small molecules using the UCSF DOCK 6.1
program suite and the NCI chemical library database. We discovered two novel BAK activators (BKA-073 and
BKA-758) that exhibit selective apoptotic effect in lung cancer cells as compared to normal human bronchial
epithelial cells. Fluorescence polarization assay reveals that BKA-073 and BKA-758 preferentially bind to BAK
protein with inhibitory constant (Ki) values at nanomolar levels in vitro but do not bind to other Bcl2 family
members (i.e. BAX or Bcl2). The lead compound BKA-758 has potent antitumor activity against lung cancer in
xenografts derived from lung cancer cell lines or patient-derived xenograft models. We hypothesize that
BKA(s) may specifically activate the proapoptotic function of BAK in tumor cells by specifically targeting its BH3
binding pocket, which leads to suppression of lung cancer. To test this hypothesis, we have identified two
specific aims: (1) To determine the mechanism(s) by which BAK agonists (BKAs) activate the proapoptotic
function of BAK and induce apoptosis in human lung cancer cells; (2) To determine whether BKA compounds
suppress the growth of small lung cancer (SCLC) and non-small cell lung cancer (NSCLC) in vivo. Studies will
test the potency of BKAs in patient-derived xenografts, radioresistant lung cancer and genetically engineered
lung cancer animal models. Determine whether the “dynamic BH3 profiling” predicts the antitumor efficacy of
BKA compounds in vivo. Based on our proposed studies, it is expected that novel first-in-class BAK agonists
as an entirely new class of anti-lung cancer drugs will be developed for lung cancer therapy.

## Key facts

- **NIH application ID:** 9830593
- **Project number:** 5R01CA200905-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Xingming Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830593

## Citation

> US National Institutes of Health, RePORTER application 9830593, Modulation of BAK in Lung Cancer Therapeutics (5R01CA200905-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9830593. Licensed CC0.

---

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