Discovery of Potent and Selective PI3Kγ Inhibitors.


:The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes 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 PI3Kγ inhibitors 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 PI3Kγ over 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.


J Med Chem


Drew SL,Thomas-Tran R,Beatty JW,Fournier J,Lawson KV,Miles DH,Mata G,Sharif EU,Yan X,Mailyan AK,Ginn E,Chen J,Wong K,Soni D,Dhanota P,Chen PY,Shaqfeh SG,Meleza C,Pham AT,Chen A,Zhao X,Banuelos J,Jin L,Schind




Has Abstract


2020-10-08 00:00:00












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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Loew GH,Jester JR

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    pub_type: 杂志文章


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    更新日期:2013-07-25 00:00:00

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    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Yu Q,Greig NH,Holloway HW,Brossi A

    更新日期:1998-06-18 00:00:00

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    abstract::A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induce...

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    pub_type: 杂志文章


    authors: Kamakolanu UG,Meyer ME,Yasuda D,Polgar WE,Marti M,Mercatelli D,Pisanò CA,Brugnoli A,Morari M,Zaveri NT

    更新日期:2020-03-12 00:00:00