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1.
Chem Sci ; 15(2): 683-691, 2024 Jan 03.
Article in English | MEDLINE | ID: mdl-38179525

ABSTRACT

Class I phosphoinositide 3-kinases (PI3Ks) control cellular growth, but are also essential in insulin signaling and glucose homeostasis. Pan-PI3K inhibitors thus generate substantial adverse effects, a reality that has plagued drug development against this target class. We present here evidence that a high affinity binding module with the capacity to target all class I PI3K isoforms can facilitate selective degradation of the most frequently mutated class I isoform, PI3Kα, when incorporated into a cereblon-targeted (CRBN) degrader. A systematic proteomics study guided the fine tuning of molecular features to optimize degrader selectivity and potency. Our work resulted in the creation of WJ112-14, a PI3Kα-specific nanomolar degrader that should serve as an important research tool for studying PI3K biology. Given the toxicities observed in the clinic with unselective PI3Kα inhibitors, the results here offer a new approach toward selectively targeting this frequently mutated oncogenic driver.

3.
Eur J Med Chem ; 248: 115038, 2023 Feb 15.
Article in English | MEDLINE | ID: mdl-36634458

ABSTRACT

Upregulation of mechanistic target of rapamycin (mTOR) signaling drives various types of cancers and neurological diseases. Rapamycin and its analogues (rapalogs) are first generation mTOR inhibitors, and selectively block mTOR complex 1 (TORC1) by an allosteric mechanism. In contrast, second generation ATP-binding site inhibitors of mTOR kinase (TORKi) target both TORC1 and TORC2. Here, we explore 3,6-dihydro-2H-pyran (DHP) and tetrahydro-2H-pyran (THP) as isosteres of the morpholine moiety to unlock a novel chemical space for TORKi generation. A library of DHP- and THP-substituted triazines was prepared, and molecular modelling provided a rational for a structure activity relationship study. Finally, compound 11b [5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine] was selected due its potency and selectivity for mTOR kinase over the structurally related class I phosphoinositide 3-kinases (PI3Ks) isoforms. 11b displayed high metabolic stability towards CYP1A1 degradation, which is of advantage in drug development. After oral administration to male Sprague Dawley rats, 11b reached high concentrations both in plasma and brain, revealing an excellent oral bioavailability. In a metabolic stability assay using human hepatocytes, 11b was more stable than PQR620, the first-in-class brain penetrant TORKi. Compound 11b also displayed dose-dependent anti-proliferative activity in splenic marginal zone lymphoma (SMZL) cell lines as single agent and when combined with BCL2 inhibition (venetoclax). Our results identify the THP-substituted triazine core as a novel scaffold for the development of metabolically stable TORKi for the treatment of chronic diseases and cancers driven by mTOR deregulation and requiring drug distribution also to the central nervous system.


Subject(s)
Neoplasms , TOR Serine-Threonine Kinases , Rats , Animals , Male , Humans , Rats, Sprague-Dawley , TOR Serine-Threonine Kinases/metabolism , Mechanistic Target of Rapamycin Complex 1 , Morpholines/pharmacology , Morpholines/chemistry , Sirolimus/pharmacology , Sirolimus/therapeutic use , Neoplasms/drug therapy , Pyrans/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
4.
J Med Chem ; 63(22): 13595-13617, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33166139

ABSTRACT

The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi. An extensive investigation of the morpholine ring engaging the mTOR solvent exposed region led to the discovery of PQR626 (8). 8 displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated Tsc1 gene in glia, 8 significantly reduced the loss of Tsc1-induced mortality at 50 mg/kg p.o. twice a day. 8 overcomes the metabolic liabilities of PQR620 (52), the first-in-class brain penetrant TORKi showing efficacy in a TSC mouse model. The improved stability in human hepatocytes, excellent brain penetration, and efficacy in Tsc1GFAPCKO mice qualify 8 as a potential therapeutic candidate for the treatment of neurological disorders.


Subject(s)
Brain/metabolism , Morpholines/administration & dosage , Morpholines/metabolism , Nervous System Diseases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Administration, Oral , Animals , Brain/drug effects , Dogs , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Morpholines/chemistry , Nervous System Diseases/drug therapy , Rats , Rats, Sprague-Dawley
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