1935921-64-4Relevant articles and documents
Discovery of Potent and Selective PI3KγInhibitors
Drew, Samuel L.,Thomas-Tran, Rhiannon,Beatty, Joel W.,Fournier, Jeremy,Lawson, Kenneth V.,Miles, Dillon H.,Mata, Guillaume,Sharif, Ehesan U.,Yan, Xuelei,Mailyan, Artur K.,Ginn, Elaine,Chen, Jie,Wong, Kent,Soni, Divyank,Dhanota, Puja,Chen, Pei-Yu,Shaqfeh, Stefan G.,Meleza, Cesar,Pham, Amber T.,Chen, Ada,Zhao, Xiaoning,Banuelos, Jesus,Jin, Lixia,Schindler, Ulrike,Walters, Matthew J.,Young, Stephen W.,Walker, Nigel P.,Leleti, Manmohan Reddy,Powers, Jay P.,Jeffrey, Jenna L.
, p. 11235 - 11257 (2020/11/09)
The selective inhibition of the lipid signaling enzyme PI3Kγconstitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγinhibitors that attain high isoform selectivity through the divergent projection of substituents into both the selectivity and alkyl-induced pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγover the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an alkyl-induced pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.
PYRIDAZINONES AS PARP7 INHIBITORS
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Paragraph 0671, (2019/11/11)
The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.
PYRROLO-, PYRAZOLO-, IMIDAZO-PYRIMIDINE AND PYRIDINE COMPOUNDS THAT INHIBIT MNK1 AND MNK2
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Paragraph 0274, (2017/06/02)
The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds A1, A2, A3, A4, A5, A6, A7, W1, R1, R2, R3, R4, R5a, R5b, R6, R7, R7a, R7b, R8, R8a, R8b, R9, R9a, R9b and R10 and subscripts “m” and “n” are as defined in the specification. The inventive Formula I compounds are inhibitors of Mnk and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
