T. Matthew Hansen

Highly chemoselective oxidation of 1,5-diols to δ-lactones with TEMPO/BAIB

Abstract The selective oxidative conversion of a variety of highly functionalized 1°,2°-1,5-diols into the corresponding δ-lactones has been effected simply and efficiently using a reagent system comprised of catalytic 2,2,6,6-tetrmethylpiperidinooxy (TEMPO) and excess bis-acetoxyiodobenzene (BAIB).

Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Strategy and Component Assembly

The phorboxazole natural products are among the most potent inhibitors of cancer cell division, but they are essentially unavailable from natural sources at present. Laboratory syntheses based upon tri-component fragment coupling strategies have been developed that provide phorboxazole A and analogues in a reliable manner and with unprecedented efficiency. This has been orchestrated to occur via the sequential or simultaneous formation of both of the natural products oxazole moieties from two serine-derived amides, involving oxidation-cyclodehydrations. The optimized preparation of three pre-assembled components, representing carbons 3-17, 18-30, and 31-46, has been developed. This article details the design and syntheses of these three essential building blocks. The convergent coupling approach is designed to facilitate the incorporation of structural changes within each component to generate unnatural analogues, targeting those with enhanced therapeutic potential and efficacy.

Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis.

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural products (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural products oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

Abstract 3059: Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry

As part of a multi-year technology integration strategy to identify unprecedented targets, AbbVie has committed to building broad-endpoint profiling assays to enable phenotypic screening campaigns and compound prioritization. Early on, phenotypic cell-based screening employing a panel of protein-fragment complementation assays (PCAs) identified A-1107604 as a hit with potent activity against a subset of endpoints. While its activity profile had some commonalities with known anti-cancer agents, the overall profile of PCAs that were significantly and concomitantly modulated represented a unique signature. Further analysis revealed A-1107604 to have potent and selective activity in a panel of human tumor cell lines. Inhibitor affinity capture from cellular lysates coupled with mass spectrometry identified the BET family of proteins as the putative cellular targets of A-1107604. Binding was localized to the bromodomain of the target proteins using affinity capture-protease digestion and was confirmed by thermal shift assay, solution binding and X-ray crystallography. This binding was found to be highly selective when A-1107604 was counter-screened against a 150-member kinase panel and an 80-member receptor panel. To correlate target affinity with cellular efficacy, a series of analogs were prepared with affinities spanning 3 orders magnitude. Affinity for BRD4, a BET family member, strongly correlated with efficacy in human tumor cell lines. Finally, A-1107604 was evaluated in human tumor xenograft models where it demonstrated significant tumor growth inhibition. This discovery effort laid the foundation for our BET inhibitor program. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Scott E. Warder, Shaun M. McLoughlin, T. Matthew Hansen, Paul L. Richardson, Denise M. Wilcox, Sadiya N. Addo, Hua Tang, Chaohong Sun, Andrew M. Petros, Sanjay C. Panchal, Chang H. Park, M. Shannon Duggan, Melanie J. Patterson, F. Greg Buchanan, Dong Cheng, Heather M. Davis, David J. Calderwood, Steven W. Elmore, Yu Shen. Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3059.