- Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor
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Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date.
- Huestis, Malcolm P.,Durk, Matthew R.,Eigenbrot, Charles,Gibbons, Paul,Hunsaker, Thomas L.,La, Hank,Leung, Dennis H.,Liu, Wendy,Malek, Shiva,Merchant, Mark,Moffat, John G.,Muli, Christine S.,Orr, Christine J.,Parr, Brendan T.,Shanahan, Frances,Sneeringer, Christopher J.,Wang, Weiru,Yen, Ivana,Yin, Jianping,Rudolph, Joachim,Siu, Michael
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- HETEROCYCLIC GLP-1 AGONISTS
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This disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.
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Page/Page column 336-337
(2022/02/15)
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- INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
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The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
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Page/Page column 472
(2021/01/29)
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- IMIDAZOPYRIMIDINE COMPOUNDS USEFUL FOR THE TREATMENT OF CANCER
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A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein A, R3, R4, R6, and R7 are as defined herein.
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Paragraph 00245
(2018/04/12)
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- 2-(PYRIDIN-3-YL)-PYRIMIDINE DERIVATIVES AS RET INHIBITORS
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Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
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Page/Page column 31; 32
(2016/09/22)
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- TRIAZOLOPYRIMIDINE COMPOUNDS AND USES THEREOF
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A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein R1, R2, R3, R4, R5, and n are as defined herein.
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Paragraph 0466; 0467
(2016/07/27)
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- ISOINDOLINONE AND PYRROLOPYRIDINONE DERIVATIVES AS AKT INHIBITORS
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The present invention provides isoindolinone and pyrrolopyridinone derivatives, as well as their compositions and methods of use, that inhibit the activity of the serine/threonine kinase, Akt, and are useful in the treatment of diseases related to the act
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- SUBSTITUTED N-[1-CYANO-2-(PHENYL)ETHYL] 1-AMINOCYCLOALK-1-YLCARBOXAMIDE COMPOUNDS - 760
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The present invention provides compounds of formula (I) in which, n, R1, R2 and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 91-92
(2012/01/05)
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- AZA-ISOINDOLONES AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS - 613
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Compounds of formula I: wherein R1, R2, R3,R4, R5, R6, R7, R8 and n are defined in the specification, methods for using said compounds, methods for making said compoun
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- Phthalazine, aza- and diaza-phthalazine compounds and methods of use
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The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I wherein A1, A2, B, R1, R2, R3 and R4 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.
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Page/Page column 27
(2008/06/13)
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