Abstract. Population-based cohort studies have revealed that neuroleptic medications are associated with a reduced cancer risk. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have an antiproliferative or cytotoxic effect on certain cancer types. Known as a superior SSRI, escitalopram oxalate exhibits favorable tolerability with generally mild and temporary adverse events. The present study aimed to examine the effects of escitalopram oxalate on non-small cell lung cancer (NSCLC) cells. The experimental results revealed that escitalopram oxalate significantly inhibited the proliferation and invasion of A549, and H460 cells compared with BEAS-2B cells. Additionally, escitalopram oxalate significantly increased the sub-G 1 population and caspase-3 activity of A549, and H460 cells. Furthermore, escitalopram oxalate significantly induced mitochondria-dependent apoptotic signaling cascades in A549 and H460 cells, which included increases in the protein expression levels of apoptosis regulator Bax, truncated BH3-interacting domain death agonist, cytochrome c, apoptotic protease-activating factor 1, and cleaved caspase-9. These findings suggest that escitalopram oxalate could serve a therapeutic agent for the treatment of NSCLC due to its antiproliferative and apoptotic effects.

Fatty acid-binding protein-5 (FABP5) or epidermal FABP belongs to a low molecular weight lipid binding protein family. FABP5 is involved in binding, storing, and transporting hydrophobic ligands to the proper cellar compartment. Recent studies have suggested that FABP5 play important roles in regulation of gene expression associated with with cell growth and differentiation. FABP5 expression level was closely related to malignency in several types of cancers. The functions of FABP5 in modulation of cellular signaling have been studies and suggested that FABP5 is involved in EGFR, NFkB and PPAR pathways. Using IMTACTM (Isobaric Mass Tagged Affinity Characterization) to screen small molecule library in live cancer cells, ligands covalently bound to FABP5 were identified. Our initial characterization of compounds showed that they specifically bind to FABP5 and inhibit cancer cell growth. These FABP5-specific covalent small molecule ligands will provide a valuable pharmacological tool to dissect FABP5 functions and shed light on the therapeutic potential of targeting FABP5 for the treatment of cancer and metabolic disorders. Citation Format: Hang Chen, Heather Ha, Robert Stanley, Cindy Huang, Qian Cai, Irene Yuan, Ping Cao. Discovery of BGS1954, a covalent small molecule ligand of FABP5 using IMTACTM platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A135. doi:10.1158/1535-7163.TARG-19-A135

BridGene Biosciences has developed a novel chemoproteomic platform IMTACTM (Isobaric Mass-Tagged Affinity Characterization) for discovering small-molecule inhibitors of protein-protein interactions, disclosing new cancer targets, and identifying previously unknown targets for known drugs. The key components of the IMTACTM platform include a unique library of drug-like covalent small molecules containing an alkyne tag, live-cell screening, and quantitative mass spec analysis. The IMTACTM analysis begins with treating live cells with probes from the covalent library, proceeds with enrichment of the probe-modified proteins, and then employs Mass Spec to identify the probe-modified proteins and determine the relative binding affinity. This powerful chemoproteomic platform enables systematic mapping of the direct interactions of small-molecules across the proteome. A prominent application of BridGene’s IMTACTM platform is to identify hits for “hard to drug” targets from live-cell screening. IMTAC TM screening is well suited for identifying drug-like ligands for such hard-to-drug targets, including those with shallow binding pockets or temporary pockets formed under certain cellular settings. Lead optimization can be immediately initiated after confirmation of the ligand’s binding to relevant targets. Using the IMTACTM platform, BridGene has discovered small-molecule ligands for a number of “hard-to-drug” targets as well as oncogenic mutants, including GTPases (e.g. RhoA), transcription factors (e.g. TEAD), splicing factors (e.g. SRSF1), epigenetic modulators (e.g. WDR5), E3 ligases, etc. The potency of the hits ranges from low nanomolar to micromolar. Because of the IMTACTM platform’s proteome-wide profiling capability, BridGene has also, for the first time, revealed new targets for some well-known drugs. Combining IMTAC TM screening with phenotypic screening, BridGene is also discovering new/unknown targets that drive certain disease phenotypic changes. IMTACTM is a novel platform to discover small molecule drugs for hard-to-drug targets. It allows the mapping of targets for small molecules on a proteome-wide scale, which can provide comprehensive selectivity information to facilitate lead optimization and lower off-target toxicity. IMTACTM has the potential to redefine precision medicine, discover new drugs and new targets, and identify new indications of known drugs. Citation Format: Cindy Huang, Vivian Zhang, Ning Deng, Irene Yuan, Linda Pullan, C. Glenn Begley, Ping Cao. A chemoproteomic platform for identifying small-molecule modulators of protein-protein interactions, discovering new cancer targets, and revealing previously unknown targets for well-known drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P098.

Guanosine monophosphate synthetase (GMPS) is a glutamine amidotransferase catalyzing amination of xanthosine monophosphate (XMP) to form GMP. It is a enzyme involved in de novo purine biosynthesis. T and B lymphocytes, and certain cancer cells, such as malignant melanoma are dependent on de novo synthesis of purine nucleotide for activation and proliferation. GMPS is an attractive target for drug discovery and development to treat autoimmune diseases, organ transplant rejection, and cancers. Mycophenolate acid (MPA), an active ingredient of Mycophenolate Mofetil (Cellcept) has been used for organ transplantation and autoimmune diseases. MPA is a natural product which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme upstream of GMPS. Using IMTACTM (Isobaric Mass Tagged Affinity Characterization) platform to perform global proteome ligand screen in live cancer cells, a highly potent and highly selective irreversible inhibitor against GMPS was discovered. Here we report the identification, in vitro characterization and in vivo evaluation of this molecule BGS2019. Target engagement of BGS2019 was determined by In-Gel-Fluorescent assay in cell with an EC50 of 15.6nM. It inhibited GMPS enzymatic activity with an IC50 of 6nM. The mechanism of BGS2019 in cell-based assays was tested, which showed the accumulation of IMP (the substrate for GMPS) and the reduction of GMP, GDP and GTP, upon BGS2019 treatment. BGS2019 was evaluated for its cell growth inhibition activity in several cancer cell lines and it suppressed cancer cell growth with IC50 values from 30nM to 100nM. In vivo administration of BGS2019 was well tolerated in mice and exhibited tumor suppression in animal model. Citation Format: Hang Chen, Heather Ha, Robert Stanley, Cindy Huang, Qian Cai, Irene Yuan, Ping Cao. Discovery of BGS2019, a highly potent and selective covalent inhibitor of GMPS using IMTACTM platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B135. doi:10.1158/1535-7163.TARG-19-B135

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