Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C 7 -C 11 dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.Peloruside A (1) is a secondary metabolite of a marine sponge (Mycale genus) collected from Pelorus Sound, New Zealand. In addition to its structure elucidation, the initial disclosure by Northcote 1 also demonstrated peloruside A to be cytotoxic to P388 murine leukemia cells at nanomolar concentrations. Subsequent investigations 2 revealed peloruside's anti-proliferation potency is similar to that exhibited by paclitaxel. The first synthesis of 1, reported by De Brabander, established the absolute stereochemistry of this natural product. 3 In the interim, two additional syntheses have been published. 4,5 The purpose of this communication is to report a convergent approach to this natural product suitable for analogue synthesis.The deconstruction of 1 relies on the two highlighted aldol disconnections illustrated in Scheme 1. Based on prior art, 6 we anticipated that the C 3 and C 15 stereocenters would favorably influence the stereochemical outcome of these two bond constructions. In the following discussion, the syntheses of subunits 3 and 4 will be described along with their elaboration to (+)-peloruside A (1). The synthesis of 5 is included in the Supplementary Information.The synthesis of C 1 -C 6 synthon 3 requires six steps from commercially available (S)-4-benzyl-2-oxazolidinone 7a and is summarized in Scheme 2. Notably, the illustrated imideevans@chemistry.harvard.edu. Supporting Information Available: Experimental details and analytical data including copies of 1 H and 13 C NMR spectra for all new compounds (xx pages) (PDF). The synthesis of methyl ketone 5 is also included. This material is available free of charge via the Internet at http://pubs.acs.org. The synthesis of synthon 4, based on the use of (S)-pantolactone, is summarized in Scheme 3. The chelate-controlled borohydride reduction was quite diastereoselective (95:5); however, competing conjugate reduction was noted as a minor side reaction. NIH Public AccessSelection of the illustrated C 9 hydroxyl configuration in subunit 4 bears comment. On the basis of previous model studies probing the influence of β-oxygen stereocenters on aldehyde face selectivity, 8 we concluded that the (R)-C 3 , (S)-C 8 and (R)-C 9 stereocenters in fragments 3 and 4 would be mutually reinforcing in this double stereodifferentiating aldol addition. A recent study by Paterson documents the diminished selectivities if the other C 9 epimer is employed in a similar aldol addition.9The aldol union of methyl ketone 3 and aldehyde 4 is summarized in Scheme 4. In developing this reaction, we noted a surprising diastereoselectivity dependence on the par...

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11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d (Ki=28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 (Ki=3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.

Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.