Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells.

We recently discovered a novel N-aryl tetracyclic dicarboximide MM0299 (1) with robust activity against glioma stem-like cells that potently and selectively inhibits lanosterol synthase leading to the accumulation of the toxic shunt metabolite 24(S),25-epoxycholesterol. Herein, we delineate a systematic and comprehensive SAR study that explores the structural space surrounding the N-aryl tetracyclic dicarboximide scaffold. A series of 100 analogs were synthesized and evaluated for activity against the murine glioma stem-like cell line Mut6 and for metabolic stability in mouse liver S9 fractions. This study led to several analogs with single-digit nanomolar activity in Mut6 glioblastoma cells that were metabolically stable in S9 fractions. In vivo pharmacokinetic analysis of selected analogs identified compound 52a (IC50 = 63 nM; S9 T1/2 > 240 min) which was orally available (39% plasma; 58% brain) and displayed excellent brain exposure. Chronic oral dosing of 52a during a 2-week tolerability study indicated no adverse effect on body weight nor signs of hematologic, liver, or kidney toxicity.

Interaction with B-type lamin reveals the function of Drosophila Keap1 xenobiotic response factor in nuclear architecture.

BACKGROUND: The Keap1-Nrf2 pathway serves as a central regulator that mediates transcriptional responses to xenobiotic and oxidative stimuli. Recent studies have shown that Keap1 and Nrf2 can regulate transcripts beyond antioxidant and detoxifying genes, yet the underlying mechanisms remain unclear. Our research has uncovered that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins can control high-order chromatin structure, including heterochromatin. METHODS AND RESULTS: In this study, we identified the molecular interaction between dKeap1 and lamin Dm0, the Drosophila B-type lamin responsible for the architecture of nuclear lamina and chromatin. Ectopic expression of dKeap1 led to an ectopic localization of lamin to the intra-nuclear area, corelated with the spreading of the heterochromatin marker H3K9me2 into euchromatin regions. Additionally, mis-regulated dKeap1 disrupted the morphology of the nuclear lamina. Knocking down of dKeap1 partially rescued the lethality induced by lamin overexpression, suggesting their genetic interaction during development. CONCLUSIONS: The discovered dKeap1-lamin interaction suggests a novel role for the Keap1 oxidative/xenobiotic response factor in regulating chromatin architecture.

Dog Life Spans and the Evolution of Aging.

AbstractThe basic tenets of the evolutionary theories of senescence are well supported. However, there has been little progress in determining the relative influences of mutation accumulation and life history optimization. The causes of the well-established inverse relationship between life span and body size across dog breeds are used here to test these two classes of theories. The life span-body size relationship is confirmed for the first time after controlling for breed phylogeny. The life span-body size relationship cannot be explained by evolutionary responses to differences in extrinsic mortality either of contemporary breeds or of breeds at their establishment. The development of breeds larger and smaller than ancestral gray wolves has occurred through changes in early growth rate. This may explain the increase in the minimum age-dependent mortality rate with breed body size and thus higher age-dependent mortality throughout adult life. The main cause of this mortality is cancer. These patterns are consistent with the optimization of life history as described by the disposable soma theory of the evolution of aging. The dog breed life span-body size relationship may be the result of the evolution of greater defense against cancer lagging behind the rapid increase in body size during recent breed establishment.

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase.

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.

High-dose oral medroxyprogesterone for inappropriate hypersexuality in elderly men with dementia: a case series.

OBJECTIVE: To retrospectively examine the utility of high-dose oral medroxyprogesterone (MPA) for the treatment of inappropriate hypersexuality (IH) in elderly men with dementia. CASE SUMMARY: Ten men aged 65 years or older (median 79.5 years, range 65-93 years) were identified from all admissions at a 170-bed tertiary referral psychiatric hospital between December 2005 and January 2011. Admission records were used to identify subjects who received at least 100 mg daily of oral MPA. The primary outcome of successful treatment was chart documentation of a substantial decline in IH, such that subjects could return to preadmission residence. Data were collected to assess trends in dose, adverse effects, use of other symptom-modifying medications prior to MPA initiation, and successful return to preadmission placement. A trial serotoneric agent was used in 70% of subjects prior to MPA initiation. Sixty percent of subjects failed a trial of an antipsychotic, while 40% did not have response to the use of both a serotonergic agent and an antipsychotic before MPA was initiated. The average daily dose of MPA was 300 mg (range 100-400 mg/day). No adverse effects were documented from physician, nursing, or behavioral health rounding notes; however, adverse effects may not have been systematically assessed at the time of MPA administration. Seventy percent of subjects experienced favorable changes in target behaviors from MPA. DISCUSSION: Few data exist on effective therapy options for treatment of IH. The minimum concentration of MPA needed to suppress IH in the male body is unknown. MPA was titrated upward, with the efficacy measure being a decrease in inappropriate behaviors. Use of MPA likely contributed to decreased IH; however, other factors involved in hospitalization could have contributed to improved behavior. CONCLUSIONS: While requiring further study, high-dose (100-400 mg/day) oral MPA may represent an effective and well-tolerated treatment option for subjects displaying IH.

Opinions and experiences of Indiana pharmacists and student pharmacists: the need for addiction and substance abuse education in the United States.

BACKGROUND: Substance abuse and addiction are growing public health problems. Pharmacists are potentially in a position to be of great assistance in ameliorating these threats yet might not be receiving the education and training to do so effectively. OBJECTIVE: To assess the relative perceived importance of substance abuse topics in pharmacy education among student pharmacists and pharmacy practitioners in the state of Indiana. METHODS: Questionnaires were administered in class to students at Purdue University College of Pharmacy and via direct mail to the home addresses of randomly selected licensed Indiana pharmacists in 2009 to elicit information on the relevance and interest for particular topics within addiction education, prior education received regarding addiction, and the frequency of professional interactions that involved addiction. RESULTS: Three hundred fifty students (74%) and 625 pharmacists (26%) responded to the survey. The average interest across all surveyed topics was 3.18/4.00 for students and 3.47/4.00 for practitioners. Areas rated highly by both groups included withdrawal, pain management, and recognition of signs and symptoms of addiction in patients. Qualitative responses from practitioners suggest strong interest in further education in this area and a perceived need for increased educational exposure during the student pharmacist experience. The average pharmacist respondent spent 6.94% of the time dealing with people who were addicted, and 22.2% had independent addiction education. CONCLUSIONS: Pharmacists and pharmacy student respondents overwhelmingly felt that educational preparation in this area is important. A significant portion of time in practice is spent managing addiction-related issues, and further educational opportunities are being pursued beyond graduation to fulfill the educational needs of the practitioner respondents.