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Your search keyword '"Haling JR"' showing total 3 results
Start Over Author "Haling JR" Topic antineoplastic agents
3 results on '"Haling JR"'

1. Design and Discovery of N -(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.

Author

Ramurthy S, Taft BR, Aversa RJ, Barsanti PA, Burger MT, Lou Y, Nishiguchi GA, Rico A, Setti L, Smith A, Subramanian S, Tamez V, Tanner H, Wan L, Hu C, Appleton BA, Mamo M, Tandeske L, Tellew JE, Huang S, Yue Q, Chaudhary A, Tian H, Iyer R, Hassan AQ, Mathews Griner LA, La Bonte LR, Cooke VG, Van Abbema A, Merritt H, Gampa K, Feng F, Yuan J, Mishina Y, Wang Y, Haling JR, Vaziri S, Hekmat-Nejad M, Polyakov V, Zang R, Sethuraman V, Amiri P, Singh M, Sellers WR, Lees E, Shao W, Dillon MP, and Stuart DD

Subjects
Animals, Antineoplastic Agents pharmacology, Drug Design, Drug Discovery trends, Humans, Molecular Docking Simulation methods, Molecular Docking Simulation trends, Mutation drug effects, Protein Kinase Inhibitors pharmacology, Xenograft Model Antitumor Assays methods, Antineoplastic Agents chemistry, Drug Discovery methods, Mutation genetics, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics
Abstract

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017 , 60 , 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15 . Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

Published
2020
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2. Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF.

Author

Shao W, Mishina YM, Feng Y, Caponigro G, Cooke VG, Rivera S, Wang Y, Shen F, Korn JM, Mathews Griner LA, Nishiguchi G, Rico A, Tellew J, Haling JR, Aversa R, Polyakov V, Zang R, Hekmat-Nejad M, Amiri P, Singh M, Keen N, Dillon MP, Lees E, Ramurthy S, Sellers WR, and Stuart DD

Subjects
2,2'-Dipyridyl pharmacology, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Female, Humans, MAP Kinase Kinase Kinases antagonists & inhibitors, Mice, Nude, Mutation, Protein Kinase Inhibitors pharmacology, Protein Multimerization, Xenograft Model Antitumor Assays, raf Kinases metabolism, 2,2'-Dipyridyl analogs & derivatives, Antineoplastic Agents pharmacology, Benzamides pharmacology, Proto-Oncogene Proteins B-raf genetics, raf Kinases antagonists & inhibitors, ras Proteins genetics
Abstract

Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAF V600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor-derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors. Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537-48. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Published
2018
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3. Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.

Author

Nishiguchi GA, Rico A, Tanner H, Aversa RJ, Taft BR, Subramanian S, Setti L, Burger MT, Wan L, Tamez V, Smith A, Lou Y, Barsanti PA, Appleton BA, Mamo M, Tandeske L, Dix I, Tellew JE, Huang S, Mathews Griner LA, Cooke VG, Van Abbema A, Merritt H, Ma S, Gampa K, Feng F, Yuan J, Wang Y, Haling JR, Vaziri S, Hekmat-Nejad M, Jansen JM, Polyakov V, Zang R, Sethuraman V, Amiri P, Singh M, Lees E, Shao W, Stuart DD, Dillon MP, and Ramurthy S

Subjects
2,2'-Dipyridyl chemistry, 2,2'-Dipyridyl pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Benzamides chemistry, Crystallography, X-Ray, Dogs, Drug Design, Drug Discovery, Drug Stability, Humans, Inhibitory Concentration 50, Mice, Molecular Targeted Therapy, Neoplasms drug therapy, Neoplasms genetics, Proto-Oncogene Proteins B-raf chemistry, Proto-Oncogene Proteins p21(ras) genetics, Rats, Structure-Activity Relationship, Xenograft Model Antitumor Assays, 2,2'-Dipyridyl analogs & derivatives, Antineoplastic Agents pharmacology, Benzamides pharmacology, raf Kinases antagonists & inhibitors, ras Proteins genetics
Abstract

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

Published
2017
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