Dr. Alexander Arnold has discovered small
molecules that can disrupt the interaction between the vitamin D receptor (VDR)
and coregulator proteins that modulate VDR-mediated gene transcription. VDR is a transcription factor, which is
activated by the binding of calcitriol and other active metabolites of vitamin
D. Small molecules with the ability to
inhibit interactions between the VDR and coregulators have the potential for
treating metabolic disorders such as chronic renal failure, skin diseases,
cancer, autoimmune disease, and heart disease.
The current problem with treatment of
metabolic disorders such as chronic renal failure, in which patients are
treated with calcitriol or synthetic vitamin D analogs, is a high risk of producing
elevated calcium in the blood (hypercalcemia).
This can lead to psychosis, bone pain, calcification of soft tissue, and
in severe cases, coma and cardiac arrest. The application of VDR-coregulator
inhibitors is advantageous due to coregulator-specific regulation of VDR target
genes. One of the most important genes
regulated by VDR is the 24-hydroxylase gene (CYP24A1), which is overexpressed
in many cancers. Many new anti-cancer
therapies are based on vitamin D analogs, but similar to the treatment of
metabolic disorders, these compounds lead to hypercalcemia and excessive excretion
of calcium in the urine of patients which can lead to impairment of renal
function. Dr. Arnold's group has
identified small molecules that act as irreversible antagonists to disrupt the
interactions between VDR and coregulators and regulate the expression of CYP24A1. The lead compounds also inhibited growth of
the prostate cancer cell line DU145, which effect was reversed by higher
concentration of calcitriol, supporting the fact that growth inhibition by coregulator
binding inhibitors is mediated by VDR. This
technology shows great promise as a drug for both cancer and metabolic
is one of the fastest growing markets at $80 billion per year. The NIH estimates that the overall costs of
cancer in 2010 were approximately $264 billion.
In 2011, about 1.6 million new cancer cases are expected to be diagnosed
and almost 600,000 Americans are expected to die of cancer. Cancer is the second most common cause of
death in the US, only exceeded by heart disease, accounting for nearly 1 in
every 4 deaths.
VDR is a nuclear receptor and this group of
proteins forms the second largest class of drug targets. The current market for
nuclear receptor targeted drugs is estimated to be 10%-15% of the global
pharmaceutical market of US $400 billion. Most of the drugs on the market that
act through the modulation of nuclear receptor activity were developed with an
incomplete understanding of the receptor that they target. Many side effects are
observed with current drugs due to lack of receptor specificity or tissue selectivity.
The Arnold laboratory's understanding of the structure and function of nuclear
receptors and coregulators and their role in health and disease will make it
possible to improve existing therapies targeting VDR and to treat several
diseases and disorders with novel, more selective drugs.
ReportsandReports.com (The Cancer Market
Outlook To 2014); www.cancer.org; Curr
Med Chem. 2008; 15(18):1802–1826;
Alexander Arnold is an Assistant Professor in the Department of Chemistry and
Biochemistry at the University of Wisconsin-Milwaukee. He obtained his Ph.D. in organic chemistry in the Department of Organic and Molecular
Inorganic Chemistryat the University of Groningen, Holland. Following his Ph.D. he conducted his post-doctoral
work at the University of California San Francisco and worked as a scientist at
St. Jude's Children's Research Hospital in Tennessee in the Department of
Chemical Biology and Therapeutics. Dr.
Arnold's laboratory investigates small molecules with the ability to inhibit
protein-protein interactions such as nuclear receptor-coregulator interactions. The Arnold Group applies high-throughput
screening, rational design, and virtual screening for the discovery process as
well as medicinal chemistry and molecular biology to determine small molecule
modes of action.
information please contact:
Jessica Silvaggi, Ph.D.
UWM Research Foundation
1440 East North Avenue
Milwaukee, WI 53202
Please reference: OTT ID. 1250
This technology is part of an active and ongoing research program and is seeking partners for development of the final product. It is available for developmental research support/licensing under either exclusive or non-exclusive terms.