Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria.

Natural killer T cells (NKT cells) recognize glycolipid antigens presented by CD1d. These cells express an evolutionarily conserved, invariant T cell antigen receptor (TCR), but the forces that drive TCR conservation have remained uncertain. Here we show that NKT cells recognized diacylglycerol-containing glycolipids from Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, and group B Streptococcus, which causes neonatal sepsis and meningitis. Furthermore, CD1d-dependent responses by NKT cells were required for activation and host protection. The glycolipid response was dependent on vaccenic acid, which is present in low concentrations in mammalian cells. Our results show how microbial lipids position the sugar for recognition by the invariant TCR and, most notably, extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.

Management instructions for elderly patients with hypertension.

Aim: To compare the understanding of hypertension and antihypertensive treatment in Japanese patients (aged <75 years vs. ≥75 years) with blood pressure (BP) targets as per the 2014 Japanese guidelines.Methods: A 10-question survey was administered before and after treatment.Results: Majority of patients aged ≥75 years did not achieve their BP targets (75%); >50% of these patients had little knowledge of hypertension and poor understanding of their physician's explanation of it.Conclusions: Elderly patients with hypertension (aged ≥75 years) require daily BP monitoring and detailed and repeated explanation of hypertension and BP targets.

Questionnaire Survey From the Viewpoint of Concordance in Patient and Physician Satisfaction Concerning Hypertensive Treatment in Elderly Patients　- Patients Voice Study.

BACKGROUND: Patient-physician concordance is an important concern in the treatment of elderly patients with hypertension (HT). Treatment that considers concordance is necessary for mutual understanding and therapeutic satisfaction between patients and physicians. However, there have been no studies addressing concordance that objectively analyzed both patient and physician satisfaction before and after treatment.Methods and Results:An exploratory open-label, multicenter, intervention study was conducted. Patients with HT undergoing treatment with angiotensin-receptor blocker (ARB) or a calcium-channel blocker (CCB) monotherapy were enrolled. Medication was switched to an ARB/CCB combination tablet and taken for 12 weeks. Physicians and patients participated in satisfaction surveys concerning treatment. Discrepancies in satisfaction levels between patients and physicians were found at baseline for the following survey items: treatment, involvement in treatment, understanding of HT, reliance, medication, and blood pressure. After treatment, the satisfaction levels of both patients and physicians increased; discrepancies in satisfaction between the groups also improved. CONCLUSIONS: The rates of satisfaction were relatively higher for patients compared with physicians at baseline. After HT treatment addressing concordance, both patient and physician satisfaction rates and the gap in satisfaction rates between patients and physicians improved. This indicates that addressing concordance has clinical significance in the treatment of elderly HT patients. (UMIN000017270).

Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice.

Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin) or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin). In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.

Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.

The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes.

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.

Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant.

The glycolipid alpha-galactosylceramide (alpha-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, alpha-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to alpha-GalCer, we performed step-wise screening assays on a focused library of 25 alpha-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than alpha-GalCer on HIV and malaria vaccines in mice.

Pharmacological Characterization of YM543, a Newly Synthesized, Orally Active SGLT2 Selective Inhibitor.

BACKGROUND AND AIM: Sodium-glucose cotransporter (SGLT) 2 is a specifically expressed transporter in the kidney that plays an important role in renal glucose reabsorption, and its inhibition may present a novel therapeutic strategy for treating diabetes. Here, we pharmacologically characterized YM543, a newly synthesized SGLT2 selective inhibitor to test this theory. RESULTS: In vitro studies revealed that YM543 potently and selectively inhibited mouse and human SGLT2 activities at nanomolar ranges. In vivo single oral administration of YM543 dose-dependently and significantly reduced blood glucose levels and improved glucose tolerance with a concomitant increase in urinary glucose excretion in KK/Ay type 2 diabetic mice, effects that were sustained even after 12 h. Repeated once-daily oral administration of YM543 for 5 weeks significantly reduced hyperglycemia in type 2 diabetic mice. In addition, combination treatment of YM543 with rosiglitazone or metformin additively improved diabetic symptoms. In contrast, YM543 did not affect normoglycemia at pharmacological doses in normal mice. CONCLUSIONS: Results from the present study suggest that YM543 is an orally active SGLT2 selective inhibitor which reduces hyperglycemia with a concomitant increase in urinary glucose excretion, indicating its promise as an effective treatment against type 2 diabetes.

The Kagoshima-DVT Score Is a Useful Predictive Model for Cancer-Associated Thrombosis in Patients With Gastrointestinal Cancer.

Background: Cancer-associated thrombosis (CAT) is a common complication of cancer and has received increasing attention; the Khorana Risk Score (KRS) is a recommended but insufficient risk assessment model for CAT. We propose a novel Kagoshima-DVT score (KDS) to predict preoperative deep vein thrombosis (DVT). This scoring method scores D-dimer ≥1.5 µg/mL, age ≥60 years, female sex, ongoing glucocorticoids, cancer with high risk of DVT, and prolonged immobility. The purpose of this study was to compare the performance of the KDS and KRS in predicting CAT in patients with gastrointestinal cancer. Methods and Results: In all, 250 patients without a history of thrombosis who received their first chemotherapy for gastrointestinal cancer were divided into low- (48.0%), intermediate- (38.8%), and high-risk (13.2%) groups for CAT development by the KDS. The patients' median age was 67 years and 63.2% were men. In all, 61 (27.1%) patients developed CAT (17.6%, 35.3%, and 36.4% of patients in the low-, intermediate, and high-risk groups, respectively; log-rank P=0.006). The area under the time-dependent receiver operating characteristic curve for CAT occurrence within 1 year was larger for the KDS than KRS (0.653 vs. 0.494). Conclusions: A high KDS at the start of first chemotherapy is a risk indicator for CAT development during chemotherapy. Moreover, the KDS is more useful than the KRS in predicting CAT risk.

Left ventricular dysfunction assessed by cardiac time interval analysis among different geometric patterns in untreated hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy is a powerful independent predictor of morbidity and mortality in hypertensive patients. Abnormal LV geometric patterns are also associated with hypertensive complications, and concentric hypertrophy is associated with the highest mortality in hypertensive patients. However, the relationship between geometric patterns and cardiac dysfunction is not fully established. We hypothesized that the Tei index, which is a measure of global cardiac function, is a feasible parameter for estimating cardiac dysfunction among the different LV geometric patterns in hypertensive patients. METHODS AND RESULTS: We enrolled 60 consecutive patients with untreated essential hypertension. Subjects were divided into 4 groups: normal geometry, concentric remodeling, eccentric hypertrophy and concentric hypertrophy. We measured ejection fraction, mitral E/A ratio, Tei index, ejection time, and isovolumic contraction and relaxation times. There were significant correlations between LV mass index and systolic blood pressure (P<0.01), ejection fraction (P<0.05), mitral E/A ratio (P<0.05) and Tei index (P<0.0001). In multiple regression analysis, only the Tei index independently correlated with LV mass index (P<0.01). Concentric hypertrophy significantly increased the Tei index compared with the other 3 groups. CONCLUSIONS: The Tei index provides a better marker for LV dysfunction by hypertensive hypertrophy than conventional parameters. LV function in concentric hypertrophy was most impaired among all the geometric patterns in untreated hypertensive patients.

Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus.

A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.

Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice.

Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 - 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin-nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes.

Evaluating the Khorana risk score of gastrointestinal cancer patients during initial chemotherapy as a predictor of patient mortality: A retrospective study.

BACKGROUND: The Khorana risk score (KRS) has been recommended for predicting the incidence of cancer-associated thrombosis (CAT). However, it has been reported KRS was not useful in predicting CAT, but rather in predicting death by setting high scores for the primary tumor site or a low prevalence of severe obesity. METHODS: A total of 260 consecutive patients with no history of thrombosis and who started initial chemotherapy for gastrointestinal cancer from January 2017 to December 2018 at our hospital were divided into three groups according to KRS; they were observed until December 2019 [122 patients (46.9%) in the low-risk group, 114 patients (43.8%) in the intermediate-risk group, and 24 patients (9.2%) in the high-risk group]. The incidence of CAT and all-cause death were compared among the three groups. RESULTS: The median age of the patients was 67 years; 63.5% were men. CAT was observed in 61 patients (26.1%); 84 patients (37.9%) died during the observation period. The incidence rate of CAT was similar among the three groups (log-rank p = 0.4); but all-cause death showed a significant difference among the three groups (high-risk group: 58.2%, intermediate-risk group: 44.6%, low-risk group: 27.5%, log-rank p = 0.002). In the multivariate analysis, the high-risk KRS group remained at increased risk for all-cause death (HR, 2.83; 95% CI, 1.37-5.83; p = 0.005), but not with CAT. CONCLUSIONS: The KRS at the start of chemotherapy for gastrointestinal cancer is not effective in predicting CAT, but it is effective in predicting prognosis in patients with gastrointestinal cancer.

NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.

Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR alpha chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Valpha14i NKT cell-deficient (Jalpha18(-/-)) BALB/c mice. On tick inoculation with B. burgdorferi, Jalpha18(-/-) mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Valpha14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Valpha14i NKT cells. Valpha14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNgamma in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Valpha14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.

Use of proton pump inhibitors is associated with an increase in adverse cardiovascular events in patients with hemodialysis: Insight from the kids registry.

BACKGROUND: Proton pump inhibitors (PPIs) are known to increase the risk of mortality and cardiovascular events in the general population. However, in patients with maintenance hemodialysis, PPI effects are under investigated. METHODS: We analyzed the risk of PPIs for cardiovascular events using the Kagoshima Dialysis (KIDS) registry, a prospective, multicenter, observational study in patients with maintenance hemodialysis in Japan. RESULTS: In all, 531 patients were enrolled from June 2015 to December 2018. One-year follow-up data were available for 376 patients (Use of PPIs at baseline (PPI group): 217 patients and without PPIs (No PPI group): 159 patients). The incidence of a composite outcome (all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke) was higher in patients in the PPI group than the No PPI group (15.2% vs. 4.4%; hazard ratio (HR): 3.65, 95% confidence interval (CI): 1.61-8.23, P = 0.002). In the multivariate analysis, even after adjustment for covariates, the use of PPIs was an independent risk factor for a composite outcome (HR: 2.38, 95% CI: 1.02-5.54, P = 0.045). We performed propensity score matching analysis as a sensitivity analysis, showing a consistent result. The incidence of bleeding showed no difference between the two groups (15.7% vs. 11.3%; HR: 1.46, 95% CI: 0.83-2.59, P = 0.19). CONCLUSIONS: These results indicate that the use of PPIs in patients with maintenance hemodialysis might increase mortality and cardiovascular events without decreasing the risk of bleeding. Therefore, it should always be analyzed if a patient truly needs PPIs.

Natural Sphingomonas glycolipids vary greatly in their ability to activate natural killer T cells.

Mouse natural killer T (NKT) cells expressing an invariant T cell antigen receptor (TCR) recognize glycosphingolipids (GSLs) from Sphingomonas bacteria. The synthetic antigens previously tested, however, were designed to closely resemble the potent synthetic agonist alpha-galactosyl ceramide (alphaGalCer), which contains a monosaccharide and a C18:0 sphingosine lipid. Some Sphingomonas bacteria, however, also have oligosaccharide-containing GSLs, and they normally synthesize several GSLs with different sphingosine chains including one with a cyclopropyl ring-containing C21:0 (C21cycl) sphingosine. Here we studied the stimulation of NKT cells with synthetic GSL antigens containing natural tetrasaccharide sugars, or the C21cycl sphingosine. Our results indicate that there is a great degree of variability in the antigenic potency of different natural Sphingomonas glycolipids, with the C21cycl sphingosine having intermediate potency and the oligosaccharide-containing antigens exhibiting limited or no stimulatory capacity.

Quantitative microarray analysis of intact glycolipid-CD1d interaction and correlation with cell-based cytokine production.

The protein CD1d binds self and foreign glycolipids for presentation to CD1-restricted T cells by means of TCR recognition and activates T(H)1 and T(H)2 chemokine release. In this study, a variety of glycolipid ligands were attached to a microarray surface and their binding with dimeric CD1d was investigated. An alpha-galactosyl ceramide (alpha-GalCer) bearing a carbamate group at the 6'-OH position was tethered to the surface, and the dissociation constant on surface with CD1d was determined to reflect the multivalent interaction. Competition assays were then used to determine the dissociation constants (Ki) of new and intact glycolipids in solution. The 4-fluorophenyloctanoyl-modified alpha-GalCer (18) was found to bind most strongly with CD1d (Ki 0.21 microM), 2 orders of magnitude stronger than alpha-GalCer and more than three times more selective than alpha-GalCer for IFN-gamma release from NKT cells. Various alpha-GalCer analogues were analyzed, and the results showed that the binding affinity of glycolipids to CD1d correlates well with IFN-gamma production but poorly with IL-4 secretion by NKT cells, suggesting that tighter binding ligands could bias cytokine release through the T(H)1 pathway.

Antidiabetic and antiobesity effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed sugar solution.

Obesity due to excessive calorie intake is a known aggravating factor contributing to the development and progression of type 2 diabetes. Recently, excessive intake of sugar-sweetened beverages has presented challenges in stemming the tide of obesity. Here, we investigated the possible effects of sugar solution intake on the antidiabetic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice that were fed ordinary drinking water, water + glucose solution, or water + sucrose solution. Under all feeding conditions, all mice exhibited type 2 diabetic symptoms, including hyperglycemia, hyperinsulinemia, and obesity; ipragliflozin subsequently improved these symptoms through increases in urinary glucose excretion. Effective dose of and response to ipragliflozin for diabetes improvement did not significantly differ by feeding condition. Further, under all feeding conditions, ipragliflozin administration resulted in significantly increased intake of both water and sugar solutions in association with increased urine volume resulting from increased urinary glucose excretion. In sugar solution-fed diabetic mice, ipragliflozin administration tended to slightly increase the proportion of sugar solution intake in total drinking volume, although not significantly so. In addition, ipragliflozin significantly decreased calorie balance, as calculated using calorie intake from food and sugar solution and calorie excretion via urinary glucose excretion. Our observation that the antidiabetic and antiobesity effects of the SGLT2 inhibitor ipragliflozin were not greatly affected by sugar solution intake in type 2 diabetic mice suggests that, in a clinical setting, ipragliflozin will remain an effective treatment for type 2 diabetic patients with excessive intake of carbohydrates.

Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice.

In this study, we investigated and compared the effects of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan on diabetes-related diseases and complications in type 2 diabetic mice. Following 4-week repeated administration to diabetic mice, all SGLT2 inhibitors showed significant improvement in diabetes-related diseases and complications, including obesity; abnormal lipid metabolism; steatohepatitis; inflammation; endothelial dysfunction; and nephropathy. While all SGLT2 inhibitors exerted comparable effects in reducing hyperglycemia, improvement of these diabetes-related diseases and complications was more potent with the two long-acting drugs (ipragliflozin and dapagliflozin) than with the four intermediate-acting four drugs (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin), albeit without statistical significance. These findings demonstrate that SGLT2 inhibitors alleviate various diabetic pathological conditions in type 2 diabetic mice, and suggest that SGLT2 inhibitors, particularly long-acting drugs, might be useful not only for hyperglycemia but also in diabetes-related diseases and complications, including nephropathy in type 2 diabetes.

(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.