Search

The identification of a selective CDK2, 7, 9 inhibitor 4 with improved permeability is described. Compound 4 exhibits comparable CDK selectivity profile to SNS-032, but shows improved permeability and higher bioavailability in mice.

Background. Accu lturation affects health, but it has never been studied with kidney disease. Methods. W e studied the association of language spoken at home, generation and birth place with kidney function among Hispanics and Chinese in the Multi-Ethnic Study of Atherosclerosis (n = 2999). Kidney function was determined by cystatin C (eGFRcys) and albumin/creatinine ratio (ACR). We evaluated mediators in models: Model 1 = age, sex,income, education; Model 2 = Model 1 + behaviors; and Model 3 = Model 1 + comorbidities. Results. A mong Hispanics, speaking mixed Spanish/ English was significantly associated with lower eGFRcys (−2 .83 mL/min/1.73 m 2 , −5.69–0.04) and higher ACR (RD 40%, 17–68%) compared with speaking Spanish only; this was mildly attenuated by behaviors (−2.2 9, −5.33–0.75; RD 42%, 18–72%) but not comorbidities (−3.04, −5.83 to −0.23); RD 35%, 14–59%). US-born Hispanics had lower eGFRcys compared with foreign-born Hispanics [1.83 mL/min/1.73 m 2 lower (0.97–1.31) for Generation 1; 1.37 mL/min/1.73 m 2 lower (0.75–1.57) for Generation ≥2]. In contrast, Chinese who spoke any English had higher eGFRcys (2.53, 95% CI: −1. 70–6.78), but similar ACR (RD −5%, 95% CI: −26–23%) compared with those speaking Chinese only, but associations were not statistically significant. Conclusion. Hi gher acculturation was associated with worse kidney function in Hispanics, mediated perhaps by behavioral factors but not comorbidities. Associations may be in the opposite direction among Chinese. Future studies are needed to elucidate these mechanisms.

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors. Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors. Results: In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm3. In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA. Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.

Modifications of the isonipecotic acid fragment of SNS-032 results in analogs which are more permeable and lower effluxed than SNS-032. The enantiomerically pure synthesis and the in vivo profile of analog 20 is described.