Uppsala universitet,Umeå universitet,Urologi och andrologi,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden,Urologkirurgi,Umea Univ Hosp, Dept Surg & Perioperat Sci, Urol & Androl, Umea, Sweden
Ivanov, Vladimir (författare)
Enamine Ltd, Kiev, Ukraine.
Colinge, Jacques (författare)
Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Univ Montpellier, Fac Med, Montpellier, France.;Inst Reg Canc Montpellier, INSERM U1194, Inst Rech Cancerol Montpellier, Montpellier, France.
Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.
Ämnesord
MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
NATURVETENSKAP -- Kemi -- Biokemi (hsv//swe)
NATURAL SCIENCES -- Chemical Sciences -- Biochemistry (hsv//eng)