1065075-68-4Relevant articles and documents
Design and Development of a Chemical Probe for Pseudokinase Ca2+/calmodulin-Dependent Ser/Thr Kinase
Aydogan, Yagmur,Berger, Benedict-Tilman,Chaikuad, Apirat,Drewry, David H.,Knapp, Stefan,Müller, Susanne,Mandel, Sebastian,Mauer, Sandy,Pohl, Christian,Russ, Nadine,Schr?der, Martin
, p. 14358 - 14376 (2021/10/12)
CASK (Ca2+/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which
Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy
Nissink, J. Willem M.,Bazzaz, Sana,Blackett, Carolyn,Clark, Matthew A.,Collingwood, Olga,Disch, Jeremy S.,Gikunju, Diana,Goldberg, Kristin,Guilinger, John P.,Hardaker, Elizabeth,Hennessy, Edward J.,Jetson, Rachael,Keefe, Anthony D.,McCoull, William,McMurray, Lindsay,Olszewski, Allison,Overman, Ross,Pflug, Alexander,Preston, Marian,Rawlins, Philip B.,Rivers, Emma,Schimpl, Marianne,Smith, Paul,Truman, Caroline,Underwood, Elizabeth,Warwicker, Juli,Winter-Holt, Jon,Woodcock, Simon,Zhang, Ying
, p. 3165 - 3184 (2021/04/06)
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.
Structure optimization of positive allosteric modulators of GABAB receptors led to the unexpected discovery of antagonists/potential negative allosteric modulators
Mugnaini, Claudia,Brizzi, Antonella,Mostallino, Rafaela,Castelli, Maria Paola,Corelli, Federico
, (2020/08/06)
Positive allosteric modulators (PAMs) of GABAB receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABAB receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 μM GABA using [35S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.
