Hilmar Weinmann

Efficient and environmentally friendly synthesis of 2-amino-imidazole

Abstract A new and efficient method for the preparation of 2-amino-imidazole 3 was developed. Starting from cheap commodities O -methyl-iso-urea sulphate and 2-aminoacetaldehyde-acetales the desired product is isolated through a very simple work-up in a good yield. This new procedure overcomes several technical and environmental problems of the traditional approaches to this molecule and is therefore very attractive for large-scale preparation.

Editorial: Drug Discovery Process for Kinease Inhibitors

This special issue of ChemBioChem contains peer-reviewed contributions devoted to “Kinases in Drug Discovery”. With more than 518 kinases in the human kinome and the overall costs of new drug development rapidly approaching the billion dollar mark, there is a great need for focused strategies and technologies to move kinase drug discovery forward in a more rapid and efficient manner. The major goal of this special issue is to outline trends in kinase-inhibitor research organized along the drug-discovery process.

A mild and efficient dehydrogenation of indolines

Abstract A new mild and efficient dehydrogenation of indolines to indoles has been developed. For the dehydrogenation trichloroisocyanuric acid is used in combination with DBU. After work-up with sodium hydrogen sulfite it was possible to obtain indole in an almost quantitative yield. The new method is also suitable for indolines bearing electron withdrawing or electron donating groups. Under the reaction conditions no ring chlorination was observed.

Histone deacetylase inhibitors: a survey of recent patents

Histone deacetylase (HDAC) inhibitors have been the subject of an intense drug discovery effort in the pharmaceutical industry and in some academic institutions over the last few years. Although, at present, only a small number of compounds have progressed to human clinical trials, the prospect of finding safe compounds useful in therapy, particularly in cancer and inflammatory processes, is still a strong motivating factor for further research efforts. A patent literature review of small organic molecules as HDAC inhibitors is presented here, as many of the major pharmaceutical companies have shown a continued effort in the field [1]. This paper provides an update on the patenting activity in 2004 – 2005 related to HDAC inhibitors.

Recent Advances in Medicinal Chemistry of Histone Deacetylase Inhibitors

Publisher Summary Histone deacetylases (HDACs) inhibitors induce histone hyperacetylation, reactivate suppressed genes and consequently, inhibit the cell cycle, activate differentiation programmes or induce apoptosis and several HDAC inhibitors of various structural families have now advanced into phase I and II clinical trials. Mammalian HDACs can be divided into three distinct classes. Class I deacetylases, HDACs 1, 2, 2, 8, share homology in their catalytic sites with molecular weights of 42–55 kDa. Class II deacetylases includes HDACs with molecular weights between 120–130 kDa. The third class of deacetylases is the conserved Sir2 family of proteins which are dependent on NAD + for activity whereas Class I and II HDACs operate by zinc-dependent mechanisms. HDAC inhibitors bear great potential as new drugs because of their ability to modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apoptogenic properties. Furthermore the anticancer activity of HDAC inhibitors may be mediated in part by the inhibition of angiogenesis, since it was shown recently that TSA specifically inhibited hypoxia-induced angiogenesis by reducing the expression of genes required for angiogenesis. Several structural classes of compounds have been described as HDAC inhibitors. The most important of these compound classes are short-chain fatty acids, hydroxamic acids, benzamides, and cyclic tetrapeptides.

Synthesis of 7a-substituted Hajos-Wiechert ketone analogues.

A general and efficient route to 2-substituted 1,3-cyclopentadiones 3 has been developed. This operationally simple, two-step procedure is amenable to multigram scale preparations of these useful synthetic intermediates. These compounds are then transformed to previously unknown, higher analogues of the Hajos-Parrish-Eder-Sauer-Wiechert ketone (enone 1, R = Me) following an enantioselective Robinson annulation.

EFFICIENT SYNTHESIS OF THE GADOLINIUM COMPLEX OF A NEW C2-SYMMETRIC TETRAMINE

Abstract A short and efficient synthesis of the substituted tetramines 2a and 7 and of the gadolinium complex 1 was developed starting from the Cbz-protected amino alcohol 3 . Key steps of the synthesis are the optimized bleach oxidation of enantiopure alcohols and the bridging of the resulting aldehyde molecules by double reductive amination with ethylenediamine. Interesting biological activity of the amines 2a and 7 was detected.

Recent patent trends in the field of progesterone receptor agonists and modulators

Background: Progesterone receptor agonists are used in female contraception, hormone replacement therapy or some gynecological conditions like endometriosis. The interest for antagonists or selective progesterone receptor modulators (SPRMs) is growing. Recent reports on this class of compounds indicate that they could become the next generation of therapeutics in gynecological treatments. Objective: This overview summarizes the work on progesterone receptor agonists, SPRMs and antagonists reported in the patent literature in the past 4 years. Methods: The focus of the article is the examination of patents, primarily published as WO, EU or US patents since 2005. In some cases, additional data from the public literature is included into the discussion. These data are of substantial interest as the available biological data disclosed in patents are usually limited for new compound classes. Results/conclusion: Some highly active clusters of compounds have been disclosed in the past 4 years. The current research seems to focus on SPRMs and progesterone receptor antagonists.

Abstract 5239: Probing the cancer epigenome: empowering target validation by open innovation

Low reproducibility of published target validation studies as well as the frequent failure of genetic knock-down effects to phenocopy those of small molecule inhibitors have been recognized as road blocks for cancer drug discovery. Academic and industrial institutions have started to address these issues by providing access to high quality small molecular probes for novel targets of interest. Here we discuss probe discovery challenges and quality criteria based on the generation of three novel inhibitors for epigenetic targets. ATAD2 (ATPase family AAA-domain containing protein 2) is an epigenetic regulator that binds to chromatin through its bromodomain (BD). ATAD2 has been proposed to act as a co-factor for oncogenic transcription factors such as ERα and Myc. A more thorough validation of ATAD2 as a therapeutic target has been hampered by the lack of appropriate ATAD2 inhibitors. Here we disclose a structurally unprecedented series of ATAD2 BD inhibitors identified from a DNA-encoded library screen. Optimization delivered BAY-850, a highly potent and exceptionally selective ATAD2 BD inhibitor, which fully recapitulates effects seen by genetic mutagenesis studies in a cellular assay. The three BD and PHD-finger (BRPF) family members are found in histone acetyltransferase complexes. Whereas bromodomain inhibitors with dual activity against BRPF1 and 2 have been described before, we now disclose BAY-299, the first nanomolar inhibitor of the BRPF2 BD with high selectivity against its paralogs. Isoform selectivity was confirmed in cellular protein-protein interaction assays and rationalized based on X-Ray structures. BAY-598, a highly selective, cellularly active and orally bioavailable inhibitor of the protein lysine methyl transferase SMYD2, had been disclosed previously (Stresemann et al., AACR 2015). Development of BAY-598 allowed the identification of new methylation targets of SMYD2 as well as a proposed role of SMYD2 in pancreatic cancer. These results support further development of small molecule inhibitors as research tools to probe the functional role of novel epigenetic targets and underscore the power of open innovation for advancing our understanding of cancer target biology. Citation Format: Ingo V. Hartung, Cheryl Arrowsmith, Volker Badock, Naomi Barak, Markus Berger, Peter J. Brown, Clara D. Christ, Erik Eggert, Ursula Egner, Oleg Fedorov, Amaury E. Fernandez-Montalvan, Matyas Gorjanacz, Andrea Haegebarth, Bernard Haendler, Roman C. Hillig, Simon H. Holton, Kilian V. Huber, Seong J. Koo, Antonius ter Laak, Susanne Mueller, Anke Mueller-Fahrnow, Cora Scholten, Stephan Siegel, Timo Stellfeld, Detlef Stoeckigt, Carlo Stresemann, Masoud Vedadi, Joerg Weiske, Hilmar Weinmann. Probing the cancer epigenome: empowering target validation by open innovation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5239. doi:10.1158/1538-7445.AM2017-5239

Abstract 5084: Potent and isoform-selective ATAD2 bromodomain inhibitor with unprecedented chemical structure and mode of action

ATAD2 (ATPase family AAA-domain containing protein 2, also called ANCCA) is an epigenetic regulator that binds to chromatin through its bromodomain (BD), a motif specialized for acetyl-lysine recognition. ATAD2 directly associates with multiple transcription factors such as ERα, AR, E2F, and Myc; hence, ATAD2 has been proposed to act as a co-factor for oncogenic transcription factors. Furthermore, we have recently reported a novel role for ATAD2 during DNA replication, uncovering interactions between ATAD2 and histone acetylation marks on newly synthesized histone H4. High expression of ATAD2 strongly correlates with poor patient prognosis in multiple tumor types, including gastric, endometrial, hepatocellular, ovarian, breast and lung cancers. However, the exact function of ATAD2 in these tumor types remains unclear. A more thorough validation of ATAD2 as a therapeutic target is hampered by the lack of isoform-selective, potent and cellularly active ATAD2 inhibitors. A systematic assessment of crystal structures of BD-containing protein family predicted that development of selective inhibitors of ATAD2 would be challenging. In line with this prediction, only limited progress in developing lead compounds targeting ATAD2 has been reported so far. A few notable exceptions relied on fragments as starting points, however, their weak potency, insufficient selectivity against other BDs, permeability limitations or modest cellular activity have curbed their further development towards drug candidates. Here we embarked on a novel strategy to identify ATAD2 inhibitors: 11 different DNA-encoded libraries adding up to 67 billion unique encoded compounds were combined and incubated with ATAD2 BD followed by two rounds of affinity-mediated selection. This approach provided with several series of binders, for which specific target engagement of their SMOL moiety upon off-DNA synthesis was confirmed in biochemical and biophysical assays. Several rounds of potency optimization led to the identification of BAY-850, a highly potent and ATAD2 (isoform A) mono-selective inhibitor, which holds an amine substituted 3-(2-furyl)benzamide core. This compound shows - as revealed by size exclusion chromatography and native mass spectrometry - a novel mode of action for a BD inhibitor based on specific target dimerization. In a cellular fluorescence recovery after photobleaching (FRAP) assay BAY-850 displaced wild-type ATAD2 from the chromatin to the same extent as the genetic mutagenesis of ATAD2 BD. In contrast, chemically very similar inactive control compounds showed no major effects on ATAD2 association with the chromatin. These results qualify BAY-850 as the first biologically active ATAD2 isoform A-specific chemical probe, which will enable further elucidation of the cancer biology of this intriguing protein. Citation Format: Amaury E. Fernandez-Montalvan, Markus Berger, Benno Kuropka, Seong Joo Koo, Volker Badock, Joerg Weiske, Simon J. Holton, Apirat Chaikuad, Laura Diaz-Saez, James Bennett, Oleg Federov, Kilian Huber, Paolo Centrella, Matthew A. Clark, Christoph E. Dumelin, Eric A. Sigel, Holly S. Soutter, Dawn M. Troast, Ying Zhang, John W. Cuozzo, Anthony D. Keefe, Didier Roche, Vincent Rodeschini, Jan Hubner, Hilmar Weinmann, Ingo V. Hartung, Matyas Gorjanacz. Potent and isoform-selective ATAD2 bromodomain inhibitor with unprecedented chemical structure and mode of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5084. doi:10.1158/1538-7445.AM2017-5084