Preclinical Development of First-in-Class NDUFS7 Antagonists for the Treatment of Pancreatic Cancer

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Oxidative phosphorylation (OXPHOS) plays an important role in mitochondria function by mediating bioenergetics, biomass production, and redox balance, all essential processes for tumor progression, metastasis, and survival. Thus, targeting OXPHOS holds great promise to treat PDAC. Metformin, a clinically used OXPHOS inhibitor, has demonstrated increased survival in PDAC patients, suggesting that OXPHOS inhibitors can safely be used to treat PDAC. A clearer picture is now emerging on the essential role of OXPHOS in PDAC progression. For example, overexpression of OXPHOS genes correlates with poor prognosis in PDAC patients, and suppression of mitochondrial oxygen consumption significantly retards PDAC progression. Drug resistant PDAC cells ablated in KRAS are heavily dependent on OXPHOS and are sensitive to OXPHOS inhibition. Pancreatic-tumor-initiating cells also show strong reliance on OXPHOS. Importantly, OXPHOS inhibitors are synergistic with gemcitabine specifically in cells with high levels of OXPHOS-related genes. Unfortunately, metformin has low potency and poor selectivity. Other classic OXPHOS inhibitors including rotenone, antimycin A, and oligomycin, lack selectivity. We recently designed a series of highly potent OXPHOS inhibitors (DX2-201 to DX3-236). Our ADMET-guided lead optimization campaign generated over 200 novel analogues that led to the discovery of orally active OXPHOS inhibitors with nanomolar potency, acceptable toxicity, and reasonable organ distributions to advance into clinical development. We profiled a set of 105 cancer cell lines for their anti-proliferative response to DX analogues and found that our compounds profoundly inhibit the proliferation of 5 out of 7 PDAC cell lines. Through the generation of drug resistance clones, followed by whole exome sequencing, we identified NDUFS7 as the direct target of our lead compound DX2-201 in 6/6 clones. Our integrated multi-omics (RNA-seq, Bru-seq and mass spectrometry-based proteomics) studies revealed down-regulation of DNA repair genes upon DX treatment. Our DX compounds also show significant synergism with standard-of-care chemotherapy and several FDA-approved drugs. We hypothesize that OXPHOS inhibitors will provide therapeutic benefit to PDAC patients, overcome drug resistance, and could be safely and efficaciously combined with various drugs including immune checkpoint inhibitors. We will test this hypothesis through the following specific aims: Aim 1. To assess cytotoxicity of top 5 compounds as single agent and in combination with standard chemotherapy as well as several early-stage clinical candidates in a large panel of mouse and human PDAC cell lines. Aim 2. To perform MTD, full PK/PD studies, and to determine tissue distribution and accumulation of top 5 compounds in mice. Aim 3. To determine the in vivo efficacy of top 5 compounds as single agents and in combination with standard-of-care drug(s) from Aim 1 in orthotopic and GEMM models of KRAS driven pancreatic cancer.