Abstract
DHODH is a key enzyme in the biosynthesis of pyrimidines and recent studies have renewed interest in this old anti-cancer target. Here, we disclose the discovery of 4-triazolosalicylamides ...as inhibitors of DHODH and their structure activity relationship (SAR). The hit cluster was discovered during a phenotypic high throughput screen (HTS) of 2.5 million compounds where proliferation of H460 lung cancer cells was used as read-out. DHODH was successfully identified as the molecular target by comparing the activity profile of the hits in a panel of cell lines to a set of inhibitors with known pharmacological activity. The hit compounds showed good cellular potency but had undesirable DMPK properties. Interestingly, the compounds are non-ionizable in contrast to many other DHODH inhibitors and show no potency shift from biochemical to cellular assays. Structural modifications lead to compounds with sub-nanomolar potency in cellular assays and increased metabolic stability enabling the proof of concept in vivo xenograft experiments. Further optimization guided by lipophilicity efficiency and identification of metabolic hot spots resulted in molecules with low clearance and improved solubility. BAY 2402234 was selected as the clinical candidate after side by side comparison of a number of promising compounds. It shows great oral bioavailability, target engagement in all preclinical species tested, induces differentiation in AML models, and has excellent activity in a variety of leukemia models. A clinical phase I study has been initiated in patients with myeloid malignancies. (NCT03404726)
Citation Format: Stefan N. Gradl, Thomas Mueller, Steven Ferrara, Sherif El Sheikh, Andreas Janzer, Han-Jie Zhou, Anders Friberg, Judith Guenther, Martina Schaefer, Timo Stellfeld, Knut Eis, Michael Kroeber, Duy Nguyen, Claudia Merz, Michael Niehues, Detlef Stoeckigt, Sven Christian, Katja Zimmermann, Pascal Lejeune, Michael Bruening, Hanna Meyer, Vera Puetter, David T. Scadden, David B. Sykes, Henrik Seidel, Ashley Eheim, Martin Michels, Andrea Haegebarth, Marcus Bauser. Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2.
(1) on self-reported food data is commendable for both its erudition and collegial tone. Because their study was prompted, in part, by one of our own (2), we write to correct one factual point, to ...clarify substantial points of agreement between our groups, and to suggest where there is room for additional dialogue. ...consistency across studies can occur because a bias induced by measurement error, confounding, or other factors is consistently replicated.
We have used the MOST (Microvariability and Oscillations of STars) microsatellite to obtain four weeks of contiguous high-precision broad-band visual photometry of the O7.5III(n)((f)) star ... Persei ...in 2011 November. This star is well known from previous work to show prominent DACs (discrete absorption components) on time-scales of about 2 d from UV spectroscopy and non-radial pulsation with one (l = 3) p-mode oscillation with a period of 3.5 h from optical spectroscopy. Our MOST-orbit (101.4 min) binned photometry fails to reveal any periodic light variations above the 0.1 mmag 3... noise level for periods of a few hours, while several prominent Fourier peaks emerge at the 1 mmag level in the two-day period range. These longer period variations are unlikely due to pulsations, including gravity modes. From our simulations based upon a simple spot model, we deduce that we are seeing the photometric modulation of several corotating bright spots on the stellar surface. In our model, the starting times (random) and lifetimes (up to several rotations) vary from one spot to another yet all spots rotate at the same period of 4.18 d, the best-estimated rotation period of the star. This is the first convincing reported case of corotating bright spots on an O star, with important implications for drivers of the DACs (resulting from corotating interaction regions) with possible bright-spot generation via a breakout at the surface of a global magnetic field generated by a subsurface convection zone. (ProQuest: ... denotes formulae/symbols omitted.)
Changes in bone size and shape are defining features of many vertebrates. Here we use genetic crosses and comparative genomics to identify specific regulatory DNA alterations controlling skeletal ...evolution. Armor bone-size differences in sticklebacks map to a major effect locus overlapping BMP family member GDF6. Freshwater fish express more GDF6 due in part to a transposon insertion, and transgenic overexpression of GDF6 phenocopies evolutionary changes in armor-plate size. The human GDF6 locus also has undergone distinctive regulatory evolution, including complete loss of an enhancer that is otherwise highly conserved between chimps and other mammals. Functional tests show that the ancestral enhancer drives expression in hindlimbs but not forelimbs, in locations that have been specifically modified during the human transition to bipedalism. Both gain and loss of regulatory elements can localize BMP changes to specific anatomical locations, providing a flexible regulatory basis for evolving species-specific changes in skeletal form.
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•Altered armor-plate size in sticklebacks maps to a cis-regulatory change in GDF6 gene•Increased GDF6 expression phenocopies armor evolution in transgenic fish•Humans have lost a conserved regulatory element controlling GDF6 expression•Mouse phenotypes suggest that deletion is related to digit shortening in human feet
The bone morphogenetic protein gene GDF6 has evolved species-specific regulatory changes in both sticklebacks and humans, with gain and loss of particular enhancers providing a likely regulatory mechanism for changing bony armor in fish and modifying hindlimb-specific digit morphology during the transition to bipedalism in humans.
ABSTRACT Continuous photometric observations of five young stars obtained by theMOSTsatellite in 2009 and 2010 in the Taurus and Lupus star formation regions are presented. Using light-curve ...modelling under the assumption of internal invariability of spots, we obtained small values of the solar-type differential-rotation parameter (k= 0.0005-0.009) for three spotted weak-line T Tauri stars, V410 Tau, V987 Tau and Lupus 3-14; for another spotted weak-line T Tauri star (WTTS), Lupus 3-48, the data are consistent with a rigidly rotating surface (k= 0). Three flares of similar rise (4 min and 30 s) and decay (1h and 45 min) times were detected in the light curve of Lupus 3-14. The brightness of the classical T Tauri star RY Tau continuously decreased over 3 weeks of its observations with a variable modulation not showing any obvious periodic signal. PUBLICATION ABSTRACT
Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers ...have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register β-sheet structures and identifies a target for structure-based therapeutics in ALS.
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