Abstract 1895: Landmark development of PI3K delta specific inhibitors for hematologic cancer therapeutics by data-driven drug design

In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects bothin vitroandin vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted.

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OMRT-13. Delivery of Ubidecarenone (BPM 31510) to mitochondria effectuates metabolic reprogramming and redox activated apoptosis in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.037 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii9-ii9

Author(s):

Rangaprasad Sarangarajan ◽

Seema Nagpal ◽

Jiaxin Sun ◽

Anne Diers ◽

Punit Shah ◽

...

Keyword(s):

Phase 1 ◽

Metabolic Stress ◽

Network Models ◽

Cancer Therapeutics ◽

Progression Free Survival ◽

Metabolic Reprogramming ◽

Data Driven ◽

Phase 2 Trial ◽

Anti Cancer ◽

Data Driven Approach

Abstract GBM is a highly metabolic cancer phenotype that confers sustained growth and evasion of cell death mechanism via mitochondrial dysregulation. Efforts to re-engage mitochondrial metabolism via anti-cancer therapeutics has not been successful. BPM 31510 is a CoQ10-lipid conjugate nanodispersion for delivery of CoQ10 preferentially to mitochondria of human cells. BPM has demonstrated anti-cancer effects across multiple cancers, without adversely affecting normal tissue. The anti-cancer mechanism of CoQ10 was elucidated by Interrogative Biology, a data-driven approach to understand disease biology, identify targets and biomarkers of disease. Specifically, oncogenic and corresponding non-disease normal cell-based models (e.g. breast, liver, prostate, kidney) were subjected to cancer specific perturbations (e.g. hypoxia, metabolic stress). Comprehensive multi-omic (genome, proteome, lipidome, metabolome) and functional endpoints data were profiled. A Bayesian artificial intelligence analytics was used to generate network models in a data driven manner to identify BPM 31510 mechanism (i.e. shift in oxygen and glucose utilization, increase in oxidative stress and apoptosis in cancer cells). BPM 31510 re-capitulated its anti-cancer effect in GBM models, including LN-229 xenograft and C6 glioma allograft, both as monotherapy and in combination with temozolomide (TMZ)/radiation. The platform generated network maps from longitudinal pharmacodynamic samples (20 samples/28 days) collected from GBM patient refractory to TMZ/radiation/bevacizumab (Phase 1, NCT03020602, Stanford) identified alterations in intermediary metabolism as drivers of Progression Free Survival (PFS) and Overall Survival (OS) in response to BPM 31510 treatment. The platform supports the ongoing Phase 2 trial of adjuvant BPM 31510 plus TMZ/radiation in newly diagnosed GBM patients and potential accelerated approval.

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