Role of Small Molecule Interactions and Multiprotein Assemblies in CYP1B1 Disease-Associated Function and Dysfunction

Grants and Contracts Details

Description

This proposal seeks to define the role of disease-associated single nucleotide polymorphisms (SNPs) in the structure, function, and protein:protein assembly of the enzyme cytochrome P450-1B1 (CYP1B1). CYP1B1 is absent or expressed at very low levels in the liver and healthy tissues while being overexpressed in tumors, giving it the title of “universal tumor antigen”. Evidence from basic science, clinical, and epidemiological studies demonstrate that CYP1B1 is involved in cancer initiation, progression, and resistance to a wide range of chemotherapeutics. In addition, several point mutations have been discovered within CYP1B1 that are associated with other disease states, particularly hereditary congenital glaucoma and hormone-driven cancers. We hypothesize that CYP1B1 subcellular localization, oligomerization, degradation, and small molecule binding are altered in cancer cells as a function of specific SNPs and environmental features, leading to damaging levels of the protein and, consequently, metabolic products that facilitate malignant progression. We further propose to develop paradigm shifting inhibitors of this enzyme that act though two distinct mechanisms: long-residencetime coordinative inhibition, and activation of CYP1B1 degradation. Reduction of CYP1B1 protein levels and activity should suppress its role in cancer progression and chemotherapy drug resistance.
StatusFinished
Effective start/end date9/1/206/30/24

Funding

  • National Institute of General Medical Sciences: $1,649,535.00

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