Author: Reddington, James P. ; Bantscheff, Marcus ; Remlinger, Katja ; Pocha, Shirin ; Gade, Stephan ; Alvarado, David ; Jansson, Keith H. ; Keles, Hakan ; Stronach, Euan A. ; Curry, Edward ; Braun, Florian ; Karpiak, Joel ; Martinez-Segura, Amalia ; Sévin, Daniel C. ; Faelth-Savitski, Maria ; Schofield, Christopher ; Bergamini, Giovanna ; Grandi, Paola ; Dvornikov, Dmytro ; Eberl, H. Christian ; Werner, Thilo ; Hennrich, Marco L. ; Duempelfeld, Birgit ; Petretich, Massimo ; Fufezan, Christian ; Coleman, Kevin ; Sweetman, Gavain M.A. ; Feng, Bin ; Wang, Zhuo ; Sharma, Geeta ; Rutkowska, Anna

AbstractAn in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism.Significance:The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance.

01 Feb 2023·Cell Chemical Biology

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production

Article

Author: Ortiz, Francisco ; De Brabander, Jef K ; Corley, Chase D ; Wang, Xiaoyu ; Abdullah, Kalil G ; McDonald, Jeffrey G ; Lim, Sang-Kyun ; Sternisha, Alex C ; Wang, Wentian ; Nguyen, Thu P ; Nijhawan, Deepak ; Williams, Noelle S ; Parada, Luis F ; McBrayer, Samuel K ; Wang, Hua-Yu Leo

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.

01 Jan 2023·Journal of Cancer Science and Clinical Therapeutics

Cholesterol Biosynthesis Inhibitor RO 48-8071 Suppresses Growth of Epithelial Ovarian Cancer Cells in Vitro and In Vivo

Article

Author: Nephew, Kenneth P ; Liang, Yayun ; Hyder, Salman M

IntroductionEpithelial Ovarian Cancer (EOC) cells express enzymes in the cholesterol biosynthetic pathway, making this pathway an attractive therapeutic target for controlling ovarian cancer. Potent small molecule inhibitors of one biosynthetic enzyme, Oxidosqualene Cyclase (OSC), have been identified, and RO 48-8071 (4'-[6-(allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for breast and prostate cancer.MethodsCell viability assays were performed to determine effects of RO 48-8071 on growth of EOC cells. Aldehyde Dehydrogenase (ALDH) assay was conducted to determine the effects of drug on reducing stem cell like properties of EOC cells. Finally, xenograft studies were performed to assess the ability of RO 48-8071 to inhibit the growth of EOC cells in vivo.ResultsWe found that short-term (24-48 h) administration of pharmacological doses of RO effectively reduced the viability of drug-resistant EOC cells (SK-OV-3 and OVCAR-3), as determined with sulforhodamine B colorimetric assays. In 7-day assays, nanomolar concentrations of RO effectively inhibited the growth of EOC cells. RO also suppressed ALDH activity, a marker of stem cells. Importantly, RO significantly suppressed growth of xenografts derived from EOC cells when given to mice intraperitoneally (20-40 mg kg^-1 day^-1) for 27 days once tumors reached 100 mm³ (controls: 336 + 60 mm³; treated: 171 + 20 mm³) with no toxicity to the experimental animals. Mechanistically, RO induced apoptosis in tumor cells in vivo as shown with immunohistochemistry.ConclusionCholesterol biosynthesis inhibitor RO 48-8071 is thus a novel and potent inhibitor of human EOC, including EOC stem cells.

100 Deals associated with RO-488071

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Indication	Highest Phase	Country/Location	Organization	Date
Castration-Resistant Prostatic Cancer	Preclinical	Switzerland	F. Hoffmann-La Roche Ltd.	01 May 2016
Castration-Resistant Prostatic Cancer	Preclinical	United States	University Of Missouri - Columbia	01 May 2016
Hormone-dependent prostate cancer	Preclinical	United States	University Of Missouri - Columbia	01 May 2016
Hormone-dependent prostate cancer	Preclinical	Switzerland	F. Hoffmann-La Roche Ltd.	01 May 2016
Hyperlipidemias	Preclinical	-	Roche Holding AG	-

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ENDO2024	Not Applicable	Triple Negative Breast Cancer	-	RO 48-8071	plugyrmyzg(wugmpxnxmy) = reduced levels of the angiogenic markers VEGF and CD-31 (blood vessels) in vivo lrvigmnjrb (kusrvwuqep ) View more	Positive	01 Jun 2024

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