Purpose: Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. The studies in the manuscript were undertaken to examine the role of AKR1C3 in AR function and CRPC.Experimental Design: LNCaP cells stably transfected with AKR1C3 and VCaP cells endogenously expressing AKR1C3 were used to understand the effect of AKR1C3 on prostate cancer cell and tumor growth in nude mice. Chromatin immunoprecipitation, confocal microscopy, and co-immunoprecipitation studies were used to understand the recruitment of AKR1C3, intracellular localization of AKR1C3 and its interaction with AR in cells, tumor xenograft, and in Gleason sum 7 CRPC tissues. Cells were transiently transfected for AR transactivation. Novel small-molecule AKR1C3-selective inhibitors were synthesized and characterized in androgen-dependent prostate cancer and CRPC models.Results: We identified unique AR-selective coactivator-and prostate cancer growth-promoting roles for AKR1C3. AKR1C3 overexpression promotes the growth of both androgen-dependent prostate cancer and CRPC xenografts, with concomitant reactivation of androgen signaling. AKR1C3 interacted with AR in prostate cancer cells, xenografts, and in human CRPC samples and was recruited to the promoter of an androgen-responsive gene. The coactivator and growth-promoting functions of AKR1C3 were inhibited by an AKR1C3-selective competitive inhibitor.Conclusions: AKR1C3 is a novel AR-selective enzymatic coactivator and may represent the first of more than 200 known nuclear hormone receptor coactivators that can be pharmacologically targeted.

Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.

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The synthesis and characterization of amido silyl complexes of tantalum(V) free of π-anionic ligands are reported. The amido silyl chloride complexes (Me 2 N) 3 Ta(SiR 3 )Cl [SiR 3 ) Si(SiMe 3 ) 3 (1a), SiPh 2 Bu t (2)] were prepared from (Me 2 N) 3 TaCl 2 and the corresponding silyllithium reagents Li(THF) 3 Si(SiMe 3 ) 3 and Li(THF) 3 SiPh 2 Bu t . The amido silyl complexes (Me 2 N) 4 Ta-(SiR 3 ) [SiR 3 ) Si(SiMe 3 ) 3 (3), SiPh 2 Bu t (4)] were synthesized by the reactions of (Me 2 N) 4 -TaCl with Li(THF) 3 SiR 3 . Complex 3 was found to react with 1 equiv of O 2 to give an oxidation product (Me 2 N) 3 Ta(η 2 -ONMe 2 )[OSi(SiMe 3 ) 3 ] (5), and the structure of 5 was confirmed by X-ray crystallography. The spectroscopic data and crystal structure determination reveal that the coordination geometry around Ta metal in 1a and 2-4 is trigonal bipyramid with silyl ligands in an equatorial position.Early-transition-metal amido complexes have attracted much attention in recent years in part because of their important applications as precursors in chemical vapor deposition of microelectronic metal nitride (MN x ) and M-Si-N ternary films as diffusion barriers in Sibased microelectronic devices. 1,2 In particular, M-Si-N ternary films, which are often amorphous, have shown better diffusion barrier properties than, e.g., TiN films that are usually polycrystalline and thus have grain boundaries for diffusion. 1c,d,2 Although numerous well-

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Colchicine binding site inhibitors (CBSIs) hold great potential in developing new generations of antimitotic drugs. Unlike existing tubulin inhibitors such as paclitaxel, they are generally much less susceptible to resistance caused by the overexpression of drug efflux pumps. The 3,4,5-trimethoxyphenyl (TMP) moiety is a critical component present in many CBSIs, playing an important role in maintaining suitable molecular conformations of CBSIs and contributing to their high binding affinities to tubulin. Previously reported modifications to the TMP moiety in a variety of scaffolds of CBSIs have usually resulted in reduced antiproliferative potency. We previously reported a potent CBSI, VERU-111, that also contains the TMP moiety. Herein, we report the discovery of a VERU-111 analogue 13f that is significantly more potent than VERU-111. The X-ray crystal structure of 13f in complex with tubulin confirms its direct binding to the colchicine site. In addition, 13f exhibited a strong inhibitory effect on tumor growth in vivo.

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