PROJECT ABSTRACT
Despite major successes in lung cancer therapy over the last two decades, there are still many patients who do
not receive any benefit from targeted or immunotherapies. This is particularly true for small cell lung cancer
(SCLC), a recalcitrant cancer for which there are currently no effective targeted therapies. Although SCLC
patients initially respond well to conventional chemo- and immune therapy, drug resistance develops rapidly
illustrating the need for new therapeutic targets and drugs. Traditional drug discovery often prioritize known
targets and operates in limited biological and chemical space. Smaller fragment-like compounds are significantly
better suited to enter previously unrecognized binding sites thereby probing uncharted biological target space and
identifying novel targets. We hypothesize that cell-based screening of fragment-like probe molecules combined
with chemoproteomics for target identification will enable the simultaneous identification of (i) novel, highly SCLC-
specific targets and (ii) new lead compounds as modulators of these targets. We propose to specifically interrogate
SCLC cells in comparison to NSCLC and non-cancerous cells and screen a library of small fragment-like
molecules. Combination with innovative proteomics technology can subsequently identify new actionable
targets, which will be functionally validated and will serve as starting points for novel SCLC-specific drug
discovery projects. Aim 1: To identify actionable targets and associated chemical hit compounds in SCLC vs
NSCLC cancer cells. We will screen a 15,000 fragment-like compound library (~estimated to the equivalent of
>100,000 lead-like compounds) in several SCLC, which represent different molecular subtypes, and control
(NSCLC and non-cancerous lung epithelial) cell lines. The most SCLC-specific or SCLC subtype-specific hits
will be validated regarding selective viability and apoptosis effects, also in combination with standard of care
chemotherapy drugs. Aim 2: To identify and validate novel and selective, actionable targets in SCLC cells. Using
a diverse panel of fragment-like compounds with ‘privileged’ BioCore motifs and SCLC-selective screening hits
from Aim 1 we will perform mass spectrometry-based chemoproteomics through UV-mediated photocrosslinking
and copper-catalyzed ‘click’ chemistry in SCLC cell lines. High confidence protein target candidates, based on
comparison with control compounds/cell lines and DEPMAP database mining, will be validated using appropriate
biochemical and signaling readouts, as well as RNAi- and CRISPR-based genetic modulation in an expanded
cell line panel. Medicinal chemistry optimization of hits will be done by 1) chemoinformatic and structure-network
similarity analysis and 2) synthesis of analogs based on the SAR of both library and synthesized compounds.
Leads will be characterized using biochemical and cell-based binding assays (e.g. affinity-immunoblotting, SPR,
nanoBRET). The expected outcome is the identification of novel SCLC- and/or SCLC subtype-specific targets
and chemical starting points for dedicated drug discovery efforts that through further elucidation of the biological
context and in vivo validation produce desperately needed new therapeutics for SCLC.
