Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Norman, Mark H.; Andrews, Kristin L.; Bo, Yanchen; Booker, Shon K.; Caenepeel, Sean; Cee, Victor J.; D’Angelo, Noel D.; Freeman, Daniel J.; Herberich, Bradley; Hong, Fang-Tsao; Jackson, Claire; Jiang, Jian; Lanman, Brian A.; Liu, Longbin; McCarter, John D.; Mullady, Erin L.; Nishimura, Nobuko; Pettus, Liping H.; Reed, Anthony B.; Miguel, Tisha San; Smith, Adrian L.; Stec, Markian M.; Tadesse, Seifu; Tasker, Andrew S.; Aidasani, Divesh; Zhu, Xiaochun; Subramanian, Raju; Tamayo, Nuria; Wang, Ling; Whittington, Douglas A.; Wu, Bin; Wu, Tian Shung; Wurz, Ryan P.; Yang, Kevin; Zalameda, Leeanne; Zhang, Nancy R.; Hughes, Paul E.

doi:10.1021/jm300846z

Cited by 45 publications

(34 citation statements)

References 39 publications

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“…After nitro group reduction and coupling with 2‐methylpyrimidine‐5‐carboxylic acid, the corresponding amide 7 was obtained. Introduction of the key benzylic piperazine motif was realized via a Suzuki‐type coupling using the preformed trifluoroborate methylpiperazine salt 8 . After Boc group deprotection and amide formation, the first final derivative 10 was obtained.…”

Section: Figurementioning

confidence: 99%

“…Introductiono ft he key benzylic piperazine motif was realizedv ia aS uzuki-type coupling using the preformed trifluoroborate methylpiperazine salt 8. [9] After Boc group deprotection and amide formation, the first final derivative 10 was obtained. Aromatic amide cleavage under basic conditions led to the versatile aniline intermediate 11,a llowing exploration of the western part.…”

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confidence: 99%

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Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists

et al. 2016

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Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed. In addition, replacement of the terminal cyclopentylamide metabolic soft spot by five-membered heterocycles was investigated. From our efforts, we identified an optimal 6,7,8-substituted imidazo[1,2-a]pyridine core system and a 5-tert-butyl-1,2,4-oxadiazole as cyclopentylamide replacement leading to compounds 10 ((S)-N-(8-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide) and 33 ((S)-N-(8-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-3-methylpiperazin-1-yl)methyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-methylpyrimidine-5-carboxamide). Both derivatives showed good pharmacological potencies in biochemical and cell-based assays combined with excellent physicochemical properties, including low to medium plasma protein binding across species. Finally, 10 and 33 were shown to be active in a rodent pharmacokinetic/pharmacodynamic (PK/PD) model after oral gavage at 15 mg kg , lowering IL-17 cytokine production in ex vivo antigen recall assays.

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Section: Figurementioning

confidence: 99%

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confidence: 99%

Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists

et al. 2016

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“…Both ZSTK474 and AMG 511 could suppress the proliferation of GBM cell lines and subcutaneous U-87 MG xenograft growth [68–70]. GDC-0032 exhibits potent anti-proliferative and anti-tumor activities in head and neck squamous cell carcinoma and uterine serous carcinomas cell lines and xenografts with PIK3CA mutations or amplifications [71, 72].…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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“…HGF treatment also exhibited evidence of PI3K pathway activation, as measured by increased pAKT levels in G361 but not A375 cells (Figure 3C). To confirm the role of PI3K pathway signaling in mediating HGF rescue, AMG 511, a selective class I PI3K inhibitor [30], was added to G361 cells rescued from vemurafenib or PD0325901. In both cases, PI3K inhibition attenuated the HGF-mediated rescue of MAPK pathway inhibition (Supplementary Figure 4).…”

Section: Resultsmentioning

confidence: 99%

MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor

et al. 2017

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Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma. In addition, we showed that MAPK pathway inhibition induced rapid increases in MET and GAB1 levels, providing novel mechanistic insight into how BRAFV600E mutant melanoma is primed for HGF-mediated rescue. We also determined that tumor-derived HGF, not systemic HGF, may be required to convey resistance to BRAF inhibition in vivo and that resistance could be reversed following treatment with AMG 337, a selective MET inhibitor. In summary, these findings support the clinical evaluation of MET-directed targeted therapy to circumvent resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma. In addition, the induction of MET following treatment with BRAF and MEK inhibitors has the potential to serve as a predictive biomarker for identifying patients best suited for MET inhibitor combination therapy.

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Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Cited by 45 publications

References 39 publications

Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists

Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor

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