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Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer.Significance:Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995

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Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. Significance: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies. See related commentary by Rasool et al., p. 1011. This article is highlighted in the In This Issue feature, p. 995

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Deprotonation of secondary alkane nitriles with nBuLi and addition to aryl imines gives kinetic anti-β-aminonitriles. Use of LHMDS allows reversible protonation of the reaction intermediate to give syn-β-aminonitriles. The pure diastereosiomers can be isolated in good yields, and the mechanism was elucidated.

A concise, high yielding and structurally divergent synthesis of complex 1,2,3,4-tetrahydroquinoxalines with excellent diastereoselectivity is described. A wide array of nitroalkenes and imines derived from commercially available aromatic aldehydes and 2-chloroanalines were subjected to a key reductive conjugate addition nitro-Mannich reaction to give diastereomerically pure β-nitro amines. Sequential reduction of the nitro function followed by Pd-catalyzed intramolecular N-arylation of the resultant primary amine onto the 2-chloroanailine gives highly substituted 1,2,3,4-tetrahydroquinoxalines. Non basic imines were found to participate better in the nitro-Mannich reaction if the stronger acid methanesulfonic acid was used to promote the reaction. The 3 step reaction sequence should be useful for the array synthesis of drug like scaffolds.

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates ( n = 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, Aspergillus terreus , Trichophyton rubrum , Candida albicans , Candida glabrata , Candida krusei , Cryptococcus gattii , Cryptococcus neoformans , and Rhizopus oryzae . PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo , once-daily intranasal administration of PC1244 (3.2 to 80 μg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.

In this chapter, we provide a comprehensive overview of timing. We describe the underlying concepts that comprise timing through examples and then present a range of mature, standardised and evolving techniques to improve the so-called time awareness across the full Information and Communications Technology (ICT) infrastructure over which multimedia applications operate. Although the media synchronisation community is already acutely aware of timing issues, this chapter offers some valuable insights through its holistic approach to timing.

A conjugate addition nitro-Mannich reaction followed by nitro reduction and intramolecular N-arylation gives diastereomerically pure substituted 1,2-diamine containing indolines. Placing the N-arylation cyclisation handle on the imine precursor derived from an ortho-bromine substituted aromatic aldehyde gave the corresponding β-nitroamines in 55-72% yields as single diastereoisomers. Nitro reduction was effected with modified quantities of Zn/HCl and a subsequent Pd(0) catalysed Buchwald Hartwig cyclisation gave indoline products in 40-70% yields as single diastereoisomers.

The presence of promoted Schlenk equilibria for organozinc halide species has been explicitly demonstrated by 13C NMR studies. Thus, addition of methylaluminoxane (MeAlO)n, MAO, to RZnX (R=Et, Bn, ArCH2, (CH2)3CO2Et; X=Cl, Br) leads to the formation of ZnR2 and ZnX2MAO. For EtZnCl, equilibration of ZnEt2 and ZnX2MAO is rapid at -35 degrees C; a K value of 0.19 M-1 indicates the equilibrium favours ZnEt2 (0.75-3.0 equiv MAO). Use of RZnX/MAO mixtures allows copper-catalysed 1,4-addition to 2-cyclohexenone to be achieved, but a competing cascade reaction (two subsequent Michael additions and an intramolecular aldol reaction) leads to novel tetracyclic by-products (characterised crystallographically in one case). Activation of EtZnCl is also achieved by ZnMe2 addition and the presence of intermediate EtZnMe was observed by 13C NMR spectroscopy (at equilibrium, K approximately 1). Asymmetric conjugate addition in this system can be realised (up to 92% ee for additions to 2-cyclohexenone).

Conjugate additions of [Zn(bpy*)Cl(Et)] (bpy* = 4,4'-di-tert-butyl-2,2'-bipyridine) to cyclohex-2-en-1-one are promoted by ZnMe2 in 88% ee but in moderate yield under CuI phosphoramidite catalysis. In the absence of ZnMe2 the [Zn(bpy*)Cl(Et)] is inactive indicating a Schlenk-type equilibrium. Other derivatives of [Zn(bpy*)Cl(R)] (R = Bu, 4-methylbenzyl), prepared in situ from [ZnCl(R)] and the bipyridine give low yields due to competing chloride abstraction. 13C NMR studies indicate facile organo-ligand exchange between [Zn(bpy*)(Et)2] and [Zn(bpy*)Cl2] complexes. In the presence of the bipyridine, [ZnBr(allyl)] disproportionates into [Zn(bpy*)Br2] and [Zn(bpy*)(allyl)2] species. In separate studies, simple (E)-MeCH=CHCONMeR (R = Me, OMe) α,β-unsaturated amides undergo asymmetric 1,4-addition of EtMgBr in 75-99% yield and 48-79% ee in the presence of the diphosphines JosiPhos or MeDuPhos and copper(I) sources.

A conjugate addition nitro-Mannich reaction followed by nitro reduction and intramolecular N-arylation gives diastereomerically pure substituted 1,2-diamine containing indolines. Placing the N-arylation cyclisation handle on the imine precursor derived from an ortho-bromine substituted aromatic aldehyde gave the corresponding β-nitroamines in 55–72% yields as single diastereoisomers. Nitro reduction was effected with modified quantities of Zn/HCl and a subsequent Pd(0) catalysed Buchwald Hartwig cyclisation gave indoline products in 40–70% yields as single diastereoisomers.

Sulfone substituents are found to influence the diastereoselectivity of the 1,2-addition reaction to imines (II).

11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.

This paper describes and validates an extension to the widely used Flooding Time Synchronisation Protocol (FTSP) namely Dynamic Flooding Time Synchronisation Protocol for Wireless Sensor Networks. The extension enhances FTSP by dynamically optimising communication exchange with the dual aim of conserving energy whilst improving accuracy. This optimisation is realised by altering the transmission rate of motes based on real-time monitoring and the WSN application accuracy requirements. The proposed mechanism, thus, eliminates the need with FTSP to determine and pre-configure a suitable transmission interval for a particular environment. Our results show that the proposed protocol extension can perform as well as FTSP in a stable temperature environment and can achieve similar accuracies with a much reduced (up to 75 percent) number of transmissions in an environment whereby motes are exposed to temperature fluctuations.

A practical asymmetric 1,2-addition of functionalised arylzinc halides to aromatic and aliphatic aldehydes is described by the use of aminoalcohol catalysis in the presence of AlMe(3). The process is simple to carry out, uses only commercially available reagents/ligands and provides moderate to good (80-96 % ee) enantioselectivities for a wide range of substrates. Either commercial ArZnX reagents or those prepared in situ from low cost aryl bromides can be used. In the latter case electrophilic functional groups are tolerated (CO(2)Et, CN). The reaction relies on rapid exchange between ArZnX and AlMe(3) to generate mixed organometallic species that lead to the formation of a key intermediate that is distinctly different from the classic "anti" transition states of Noyori. NMR monitoring and related experiments have been used to probe the validity of the proposed selective transition state.

Combinatorial chemistry and high throughput screening have had a profound effect upon the way in which agrochemical companies conduct their lead discovery research. The article reviews recent applications of combinatorial synthesis in the lead discovery process for new fungicides, herbicides and insecticides. The role and importance of bioavailability guidelines, natural products, privileged structures, virtual screening and X-ray crystallographic protein structures on the design of solid- and solution-phase compound libraries is discussed and illustrated.

Addition of AlMe3 to commercial THF solutions of RZnX (R = aryl, functionalised aryl, vinyl; X = Br, I) simultaneously promotes Schlenk equilibria (leading to competent nucleophiles) and the formation of an Al–Zn-ligand catalyst delivering 80–90% ee for Ar1CH(OH)Ar2 formation from aldehydes.

Conjugate additions of [Zn(bpy*)Cl(Et)] (bpy* = 4,4'-di- tert -butyl-2,2'-bipyridine) to cyclohex-2-en-1-one are promoted by ZnMe 2 in 88% ee but in moderate yield under Cu I phosphoramidite catalysis. In the absence of ZnMe 2 the [Zn(bpy*)Cl(Et)] is inactive indicating a Schlenk-type equilibrium. Other derivatives of [Zn(bpy*)Cl(R)] (R = Bu, 4-methylbenzyl), prepared in situ from [ZnCl(R)] and the bipyridine give low yields due to competing chloride abstraction. 13 C NMR studies indicate facile organo-ligand exchange between [Zn(bpy*)(Et) 2 ] and [Zn(bpy*)Cl 2 ] complexes. In the presence of the bipyridine, [ZnBr(allyl)] disproportionates into [Zn(bpy*)Br 2 ] and [Zn(bpy*)(allyl) 2 ] species. In separate studies, simple ( E )-MeCH=CHCONMeR (R = Me, OMe) α,β-unsaturated amides undergo asymmetric 1,4-addition of EtMgBr in 75-99% yield and 48-79% ee in the presence of the diphosphines JosiPhos or MeDuPhos and copper(I) sources.

Addition of AlMe3 to commercial THF solutions of RZnX (R = aryl, functionalised aryl, vinyl; X = Br, I) simultaneously promotes Schlenk equilibria (leading to competent nucleophiles) and the formation of an Al-Zn-ligand catalyst delivering 80-90% ee for Ar(1)CH(OH)Ar(2) formation from aldehydes.