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23 results on '"Booker, Shon K."'

1. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors

Author

Lanman, Brian A., primary, Allen, Jennifer R., additional, Allen, John G., additional, Amegadzie, Albert K., additional, Ashton, Kate S., additional, Booker, Shon K., additional, Chen, Jian Jeffrey, additional, Chen, Ning, additional, Frohn, Michael J., additional, Goodman, Guy, additional, Kopecky, David J., additional, Liu, Longbin, additional, Lopez, Patricia, additional, Low, Jonathan D., additional, Ma, Vu, additional, Minatti, Ana E., additional, Nguyen, Thomas T., additional, Nishimura, Nobuko, additional, Pickrell, Alexander J., additional, Reed, Anthony B., additional, Shin, Youngsook, additional, Siegmund, Aaron C., additional, Tamayo, Nuria A., additional, Tegley, Christopher M., additional, Walton, Mary C., additional, Wang, Hui-Ling, additional, Wurz, Ryan P., additional, Xue, May, additional, Yang, Kevin C., additional, Achanta, Pragathi, additional, Bartberger, Michael D., additional, Canon, Jude, additional, Hollis, L. Steven, additional, McCarter, John D., additional, Mohr, Christopher, additional, Rex, Karen, additional, Saiki, Anne Y., additional, San Miguel, Tisha, additional, Volak, Laurie P., additional, Wang, Kevin H., additional, Whittington, Douglas A., additional, Zech, Stephan G., additional, Lipford, J. Russell, additional, and Cee, Victor J., additional

Published
2019
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2. Discovery of (R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies

Author

Wang, Hui-Ling, primary, Andrews, Kristin L., additional, Booker, Shon K., additional, Canon, Jude, additional, Cee, Victor J., additional, Chavez, Frank, additional, Chen, Yuping, additional, Eastwood, Heather, additional, Guerrero, Nadia, additional, Herberich, Brad, additional, Hickman, Dean, additional, Lanman, Brian A., additional, Laszlo, Jimmy, additional, Lee, Matthew R., additional, Lipford, J. Russell, additional, Mattson, Bethany, additional, Mohr, Christopher, additional, Nguyen, Yen, additional, Norman, Mark H., additional, Pettus, Liping H., additional, Powers, David, additional, Reed, Anthony B., additional, Rex, Karen, additional, Sastri, Christine, additional, Tamayo, Nuria, additional, Wang, Paul, additional, Winston, Jeffrey T., additional, Wu, Bin, additional, Wu, Qiong, additional, Wu, Tian, additional, Wurz, Ryan P., additional, Xu, Yang, additional, Zhou, Yihong, additional, and Tasker, Andrew S., additional

Published
2019
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4. Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors

Author

Lanman, Brian A., Allen, Jennifer R., Allen, John G., Amegadzie, Albert K., Ashton, Kate S., Booker, Shon K., Chen, Jian Jeffrey, Chen, Ning, Frohn, Michael J., Goodman, Guy, Kopecky, David J., Liu, Longbin, Lopez, Patricia, Low, Jonathan D., Ma, Vu, Minatti, Ana E., Nguyen, Thomas T., Nishimura, Nobuko, Pickrell, Alexander J., Reed, Anthony B., Shin, Youngsook, Siegmund, Aaron C., Tamayo, Nuria A., Tegley, Christopher M., Walton, Mary C., Wang, Hui-Ling, Wurz, Ryan P., Xue, May, Yang, Kevin C., Achanta, Pragathi, Bartberger, Michael D., Canon, Jude, Hollis, L. Steven, McCarter, John D., Mohr, Christopher, Rex, Karen, Saiki, Anne Y., San Miguel, Tisha, Volak, Laurie P., Wang, Kevin H., Whittington, Douglas A., Zech, Stephan G., Lipford, J. Russell, and Cee, Victor J.

Abstract

KRASG12Chas emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12Cto identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12Cinhibitor currently in phase I clinical trials (NCT03600883).

Published
2020
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5. Discovery of (R)‑8-(6-Methyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4‑b]-pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)-amino)-quinazolin-4(3H)‑one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological...

Author

Wang, Hui-Ling, Andrews, Kristin L., Booker, Shon K., Canon, Jude, Cee, Victor J., Chavez Jr., Frank, Chen, Yuping, Eastwood, Heather, Guerrero, Nadia, Herberich, Brad, Hickman, Dean, Lanman, Brian A., Laszlo III, Jimmy, Lee, Matthew R., Lipford, J. Russell, Mattson, Bethany, Mohr, Christopher, Nguyen, Yen, Norman, Mark H., and Pettus, Liping H.

Published
2019
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6. Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors

Author

Pettus, Liping H., primary, Andrews, Kristin L., additional, Booker, Shon K., additional, Chen, Jie, additional, Cee, Victor J., additional, Chavez, Frank, additional, Chen, Yuping, additional, Eastwood, Heather, additional, Guerrero, Nadia, additional, Herberich, Bradley, additional, Hickman, Dean, additional, Lanman, Brian A., additional, Laszlo, Jimmy, additional, Lee, Matthew R., additional, Lipford, J. Russell, additional, Mattson, Bethany, additional, Mohr, Christopher, additional, Nguyen, Yen, additional, Norman, Mark H., additional, Powers, David, additional, Reed, Anthony B., additional, Rex, Karen, additional, Sastri, Christine, additional, Tamayo, Nuria, additional, Wang, Paul, additional, Winston, Jeffrey T., additional, Wu, Bin, additional, Wu, Tian, additional, Wurz, Ryan P., additional, Xu, Yang, additional, Zhou, Yihong, additional, Tasker, Andrew S., additional, and Wang, Hui-Ling, additional

Published
2016
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7. Correction to Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Author

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

Published
2012
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8. Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

Author

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

Published
2012
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9. Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

Author

Smith, Adrian L., primary, D’Angelo, Noel D., additional, Bo, Yunxin Y., additional, Booker, Shon K., additional, Cee, Victor J., additional, Herberich, Brad, additional, Hong, Fang-Tsao, additional, Jackson, Claire L. M., additional, Lanman, Brian A., additional, Liu, Longbin, additional, Nishimura, Nobuko, additional, Pettus, Liping H., additional, Reed, Anthony B., additional, Tadesse, Seifu, additional, Tamayo, Nuria A., additional, Wurz, Ryan P., additional, Yang, Kevin, additional, Andrews, Kristin L., additional, Whittington, Douglas A., additional, McCarter, John D., additional, Miguel, Tisha San, additional, Zalameda, Leeanne, additional, Jiang, Jian, additional, Subramanian, Raju, additional, Mullady, Erin L., additional, Caenepeel, Sean, additional, Freeman, Daniel J., additional, Wang, Ling, additional, Zhang, Nancy, additional, Wu, Tian, additional, Hughes, Paul E., additional, and Norman, Mark H., additional

Published
2012
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10. Structure–Activity Relationships of Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Investigations of Various 6,5-Heterocycles to Improve Metabolic Stability

Author

Stec, Markian M., primary, Andrews, Kristin L., additional, Booker, Shon K., additional, Caenepeel, Sean, additional, Freeman, Daniel J., additional, Jiang, Jian, additional, Liao, Hongyu, additional, McCarter, John, additional, Mullady, Erin L., additional, San Miguel, Tisha, additional, Subramanian, Raju, additional, Tamayo, Nuria, additional, Wang, Ling, additional, Yang, Kevin, additional, Zalameda, Leeanne P., additional, Zhang, Nancy, additional, Hughes, Paul E., additional, and Norman, Mark H., additional

Published
2011
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11. Phospshoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Discovery and Structure–Activity Relationships of a Series of Quinoline and Quinoxaline Derivatives

Author

Nishimura, Nobuko, primary, Siegmund, Aaron, additional, Liu, Longbin, additional, Yang, Kevin, additional, Bryan, Marian C., additional, Andrews, Kristin L., additional, Bo, Yunxin, additional, Booker, Shon K., additional, Caenepeel, Sean, additional, Freeman, Daniel, additional, Liao, Hongyu, additional, McCarter, John, additional, Mullady, Erin L., additional, San Miguel, Tisha, additional, Subramanian, Raju, additional, Tamayo, Nuria, additional, Wang, Ling, additional, Whittington, Douglas A., additional, Zalameda, Leeanne, additional, Zhang, Nancy, additional, Hughes, Paul E., additional, and Norman, Mark H., additional

Published
2011
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12. Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors

Author

D’Angelo, Noel D., primary, Kim, Tae-Seong, additional, Andrews, Kristin, additional, Booker, Shon K., additional, Caenepeel, Sean, additional, Chen, Kui, additional, D’Amico, Derin, additional, Freeman, Dan, additional, Jiang, Jian, additional, Liu, Longbin, additional, McCarter, John D., additional, San Miguel, Tisha, additional, Mullady, Erin L., additional, Schrag, Michael, additional, Subramanian, Raju, additional, Tang, Jin, additional, Wahl, Robert C., additional, Wang, Ling, additional, Whittington, Douglas A., additional, Wu, Tian, additional, Xi, Ning, additional, Xu, Yang, additional, Yakowec, Peter, additional, Yang, Kevin, additional, Zalameda, Leeanne P., additional, Zhang, Nancy, additional, Hughes, Paul, additional, and Norman, Mark H., additional

Published
2011
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13. CC chemokine receptor-3 (CCR3) antagonists: Improving the selectivity of DPC168 by reducing central ring lipophilicity

Author

Pruitt, James R., Batt, Douglas G., Wacker, Dean A., Bostrom, Lori L., Booker, Shon K., McLaughlin, Erin, Houghton, Gregory C., Varnes, Jeffrey G., Christ, David D., Covington, Maryanne, Das, Anuk M., Davies, Paul, Graden, Danielle, Kariv, Ilona, Orlovsky, Yevgeniya, Stowell, Nicole C., Vaddi, Krishna G., Wadman, Eric A., Welch, Patricia K., Yeleswaram, Swamy, Solomon, Kimberly A., Newton, Robert C., Decicco, Carl P., Carter, Percy H., and Ko, Soo S.

Published
2007
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14. Design, Synthesis, and Biological Evaluation of Potent c-Met Inhibitors

Author

D’Angelo, Noel D., primary, Bellon, Steven F., additional, Booker, Shon K., additional, Cheng, Yuan, additional, Coxon, Angela, additional, Dominguez, Celia, additional, Fellows, Ingrid, additional, Hoffman, Douglas, additional, Hungate, Randall, additional, Kaplan-Lefko, Paula, additional, Lee, Matthew R., additional, Li, Chun, additional, Liu, Longbin, additional, Rainbeau, Elizabeth, additional, Reider, Paul J., additional, Rex, Karen, additional, Siegmund, Aaron, additional, Sun, Yaxiong, additional, Tasker, Andrew S., additional, Xi, Ning, additional, Xu, Shimin, additional, Yang, Yajing, additional, Zhang, Yihong, additional, Burgess, Teresa L., additional, Dussault, Isabelle, additional, and Kim, Tae-Seong, additional

Published
2008
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17. Selective Class I Phosphoinositide3-KinaseInhibitors: Optimization of a Series of Pyridyltriazines Leading tothe Identification of a Clinical Candidate, AMG 511.

Author

Norman, Mark H., Andrews, Kristin L., Bo, Yunxin Y., Booker, Shon K., Caenepeel, Sean, Cee, Victor J., D’Angelo, Noel D., Freeman, Daniel J., Herberich, Bradley J., Hong, Fang-Tsao, Jackson, Claire L. M., Jiang, Jian, Lanman, Brian A., Liu, Longbin, McCarter, John D., Mullady, Erin L., Nishimura, Nobuko, Pettus, Liping H., Reed, Anthony B., and Miguel, Tisha San

Published
2012
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18. Structure-Based Designof a Novel Series of Potent, Selective Inhibitors of the Class IPhosphatidylinositol 3-Kinases.

Author

Smith, Adrian L., D’Angelo, Noel D., Bo, Yunxin Y., Booker, Shon K., Cee, Victor J., Herberich, Brad, Hong, Fang-Tsao, Jackson, Claire L. M., Lanman, Brian A., Liu, Longbin, Nishimura, Nobuko, Pettus, Liping H., Reed, Anthony B., Tadesse, Seifu, Tamayo, Nuria A., Wurz, Ryan P., Yang, Kevin, Andrews, Kristin L., Whittington, Douglas A., and McCarter, John D.

Published
2012
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19. Phospshoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors: Discovery and Structure–Activity Relationships of a Series of Quinoline and Quinoxaline Derivatives.

Author

Nishimura, Nobuko, Siegmund, Aaron, Liu, Longbin, Yang, Kevin, Bryan, Marian C., Andrews, Kristin L., Bo, Yunxin, Booker, Shon K., Caenepeel, Sean, Freeman, Daniel, Liao, Hongyu, McCarter, John, Mullady, Erin L., San Miguel, Tisha, Subramanian, Raju, Tamayo, Nuria, Wang, Ling, Whittington, Douglas A., Zalameda, Leeanne, and Zhang, Nancy

Published
2011
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20. Discovery of a Covalent Inhibitor of KRAS G12C (AMG 510) for the Treatment of Solid Tumors.

Author

Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, and Cee VJ

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Clinical Trials as Topic, Dogs, Drug Discovery, Humans, Isomerism, Madin Darby Canine Kidney Cells, Mice, Inbred BALB C, Mice, Nude, Mutation, Piperazines chemistry, Piperazines pharmacology, Proto-Oncogene Proteins p21(ras) genetics, Pyridines chemistry, Pyridines pharmacokinetics, Pyridines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidinones chemistry, Pyrimidinones pharmacokinetics, Rats, Structure-Activity Relationship, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Piperazines therapeutic use, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Pyridines therapeutic use, Pyrimidines therapeutic use, Pyrimidinones therapeutic use
Abstract

KRAS G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS G12C inhibitor currently in phase I clinical trials (NCT03600883).

Published
2020
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21. Discovery of ( R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3 H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies.

Author

Wang HL, Andrews KL, Booker SK, Canon J, Cee VJ, Chavez F Jr, Chen Y, Eastwood H, Guerrero N, Herberich B, Hickman D, Lanman BA, Laszlo J 3rd, Lee MR, Lipford JR, Mattson B, Mohr C, Nguyen Y, Norman MH, Pettus LH, Powers D, Reed AB, Rex K, Sastri C, Tamayo N, Wang P, Winston JT, Wu B, Wu Q, Wu T, Wurz RP, Xu Y, Zhou Y, and Tasker AS

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Female, Humans, Mice, SCID, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Pyrroles chemical synthesis, Pyrroles pharmacokinetics, Quinazolinones chemical synthesis, Quinazolinones pharmacokinetics, Structure-Activity Relationship, Swine, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Pyrroles therapeutic use, Quinazolinones therapeutic use
Abstract

Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.

Published
2019
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22. Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors.

Author

D'Angelo ND, Kim TS, Andrews K, Booker SK, Caenepeel S, Chen K, D'Amico D, Freeman D, Jiang J, Liu L, McCarter JD, San Miguel T, Mullady EL, Schrag M, Subramanian R, Tang J, Wahl RC, Wang L, Whittington DA, Wu T, Xi N, Xu Y, Yakowec P, Yang K, Zalameda LP, Zhang N, Hughes P, and Norman MH

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Benzothiazoles chemistry, Benzothiazoles pharmacology, Binding Sites, Biological Availability, Cell Line, Tumor, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Female, Humans, Liver drug effects, Liver metabolism, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Rats, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Benzothiazoles chemical synthesis, Phosphoinositide-3 Kinase Inhibitors, Sulfonamides chemical synthesis, TOR Serine-Threonine Kinases antagonists & inhibitors
Abstract

Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.

Published
2011
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23. Design, synthesis, and biological evaluation of potent c-Met inhibitors.

Author

D'Angelo ND, Bellon SF, Booker SK, Cheng Y, Coxon A, Dominguez C, Fellows I, Hoffman D, Hungate R, Kaplan-Lefko P, Lee MR, Li C, Liu L, Rainbeau E, Reider PJ, Rex K, Siegmund A, Sun Y, Tasker AS, Xi N, Xu S, Yang Y, Zhang Y, Burgess TL, Dussault I, and Kim TS

Subjects
Cell Line, Tumor, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors
Abstract

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

Published
2008
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