skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

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.

Authors:
; ; ; ORCiD logo; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo « less
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405001
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 12
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Nishiguchi, Gisele A., Rico, Alice, Tanner, Huw, Aversa, Robert J., Taft, Benjamin R., Subramanian, Sharadha, Setti, Lina, Burger, Matthew T., Wan, Lifeng, Tamez, Victoriano, Smith, Aaron, Lou, Yan, Barsanti, Paul A., Appleton, Brent A., Mamo, Mulugeta, Tandeske, Laura, Dix, Ina, Tellew, John E., Huang, Shenlin, Mathews Griner, Lesley A., Cooke, Vesselina G., Van Abbema, Anne, Merritt, Hanne, Ma, Sylvia, Gampa, Kalyani, Feng, Fei, Yuan, Jing, Wang, Yingyun, Haling, Jacob R., Vaziri, Sepideh, Hekmat-Nejad, Mohammad, Jansen, Johanna M., Polyakov, Valery, Zang, Richard, Sethuraman, Vijay, Amiri, Payman, Singh, Mallika, Lees, Emma, Shao, Wenlin, Stuart, Darrin D., Dillon, Michael P., and Ramurthy, Savithri. Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.6b01862.
Nishiguchi, Gisele A., Rico, Alice, Tanner, Huw, Aversa, Robert J., Taft, Benjamin R., Subramanian, Sharadha, Setti, Lina, Burger, Matthew T., Wan, Lifeng, Tamez, Victoriano, Smith, Aaron, Lou, Yan, Barsanti, Paul A., Appleton, Brent A., Mamo, Mulugeta, Tandeske, Laura, Dix, Ina, Tellew, John E., Huang, Shenlin, Mathews Griner, Lesley A., Cooke, Vesselina G., Van Abbema, Anne, Merritt, Hanne, Ma, Sylvia, Gampa, Kalyani, Feng, Fei, Yuan, Jing, Wang, Yingyun, Haling, Jacob R., Vaziri, Sepideh, Hekmat-Nejad, Mohammad, Jansen, Johanna M., Polyakov, Valery, Zang, Richard, Sethuraman, Vijay, Amiri, Payman, Singh, Mallika, Lees, Emma, Shao, Wenlin, Stuart, Darrin D., Dillon, Michael P., & Ramurthy, Savithri. Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers. United States. doi:10.1021/acs.jmedchem.6b01862.
Nishiguchi, Gisele A., Rico, Alice, Tanner, Huw, Aversa, Robert J., Taft, Benjamin R., Subramanian, Sharadha, Setti, Lina, Burger, Matthew T., Wan, Lifeng, Tamez, Victoriano, Smith, Aaron, Lou, Yan, Barsanti, Paul A., Appleton, Brent A., Mamo, Mulugeta, Tandeske, Laura, Dix, Ina, Tellew, John E., Huang, Shenlin, Mathews Griner, Lesley A., Cooke, Vesselina G., Van Abbema, Anne, Merritt, Hanne, Ma, Sylvia, Gampa, Kalyani, Feng, Fei, Yuan, Jing, Wang, Yingyun, Haling, Jacob R., Vaziri, Sepideh, Hekmat-Nejad, Mohammad, Jansen, Johanna M., Polyakov, Valery, Zang, Richard, Sethuraman, Vijay, Amiri, Payman, Singh, Mallika, Lees, Emma, Shao, Wenlin, Stuart, Darrin D., Dillon, Michael P., and Ramurthy, Savithri. Tue . "Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers". United States. doi:10.1021/acs.jmedchem.6b01862.
@article{osti_1405001,
title = {Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -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, Gisele A. and Rico, Alice and Tanner, Huw and Aversa, Robert J. and Taft, Benjamin R. and Subramanian, Sharadha and Setti, Lina and Burger, Matthew T. and Wan, Lifeng and Tamez, Victoriano and Smith, Aaron and Lou, Yan and Barsanti, Paul A. and Appleton, Brent A. and Mamo, Mulugeta and Tandeske, Laura and Dix, Ina and Tellew, John E. and Huang, Shenlin and Mathews Griner, Lesley A. and Cooke, Vesselina G. and Van Abbema, Anne and Merritt, Hanne and Ma, Sylvia and Gampa, Kalyani and Feng, Fei and Yuan, Jing and Wang, Yingyun and Haling, Jacob R. and Vaziri, Sepideh and Hekmat-Nejad, Mohammad and Jansen, Johanna M. and Polyakov, Valery and Zang, Richard and Sethuraman, Vijay and Amiri, Payman and Singh, Mallika and Lees, Emma and Shao, Wenlin and Stuart, Darrin D. and Dillon, Michael P. and Ramurthy, Savithri},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.6b01862},
journal = {Journal of Medicinal Chemistry},
number = 12,
volume = 60,
place = {United States},
year = {Tue Jun 06 00:00:00 EDT 2017},
month = {Tue Jun 06 00:00:00 EDT 2017}
}