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1. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor

Author

Freeman-Cook, Kevin, Hoffman, Robert L., Miller, Nichol, Almaden, Jonathan, Chionis, John, Zhang, Qin, Eisele, Koleen, Liu, Chaoting, Zhang, Cathy, Huser, Nanni, Nguyen, Lisa, Costa-Jones, Cinthia, Niessen, Sherry, Carelli, Jordan, Lapek, John, Weinrich, Scott L., Wei, Ping, McMillan, Elizabeth, Wilson, Elizabeth, Wang, Tim S., McTigue, Michele, Ferre, Rose Ann, He, You-Ai, Ninkovic, Sacha, Behenna, Douglas, Tran, Khanh T., Sutton, Scott, Nagata, Asako, Ornelas, Martha A., Kephart, Susan E., Zehnder, Luke R., Murray, Brion, Xu, Meirong, Solowiej, James E., Visswanathan, Ravi, Boras, Britton, Looper, David, Lee, Nathan, Bienkowska, Jadwiga R., Zhu, Zhou, Kan, Zhengyan, Ding, Ying, Mu, Xinmeng Jasmine, Oderup, Cecilia, Salek-Ardakani, Shahram, White, Michael A., VanArsdale, Todd, and Dann, Stephen G.

Published
2021
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3. One-Pot, Metal- and Azide-Free Synthesis of 1,2,3-Triazoles from α-Ketoacetals and Amines

Author

Zehnder Luke Raymond, Sutton Scott Channing, and Joel M. Hawkins

Subjects
Metal, chemistry.chemical_compound, chemistry, Metal free, visual_art, Organic Chemistry, One-pot synthesis, visual_art.visual_art_medium, Organic chemistry, Azide
Abstract

An efficient one-pot two-step synthesis of 1,4-disubstituted 1,2,3-triazoles from α-ketoacetals and amines is presented. The method does not use metals, azides, or oxidants, and is compatible with a variety of functional groups, including heterocycles, esters, nitriles, and carbamates.

Published
2019
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4. Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer

Author

Kephart Susan Elizabeth, Tran Khanh Tuan, Kevin Daniel Freeman-Cook, Sherry Niessen, James Solowiej, Buwen Huang, Qin Zhang, Douglas Carl Behenna, Inish O'Doherty, Sacha Ninkovic, Rose Ann Ferre, Andrea Hui, Nichol Miller, Jordan Carelli, Lisa Nguyen, Brion W. Murray, Robert Louis Hoffman, John Lapek, Rhys M. Jones, Meirong Xu, Stephen Dann, Sutton Scott Channing, Asako Nagata, Nanni Huser, Ravi Visswanathan, Zehnder Luke Raymond, Elaine E. Tseng, Britton Boras, You-Ai He, Michele McTigue, Wade Diehl, Cathy Zhang, and Martha A. Ornelas

Subjects
Drug, media_common.quotation_subject, Phases of clinical research, Administration, Oral, Antineoplastic Agents, 01 natural sciences, 03 medical and health sciences, Mice, Structure-Activity Relationship, Breast cancer, Dogs, Cyclin-dependent kinase, Drug Discovery, medicine, Tumor Cells, Cultured, Animals, Humans, Protein Kinase Inhibitors, 030304 developmental biology, media_common, ADME, Cell Proliferation, 0303 health sciences, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Drug discovery, Cyclin-Dependent Kinase 2, Cancer, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Neoplasms, Experimental, Cell cycle, medicine.disease, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Injections, Intravenous, biology.protein, Cancer research, Molecular Medicine, Female, Drug Screening Assays, Antitumor
Abstract

Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.

Published
2021

5. Design and Characterization of a Pyridone-Containing EZH2 Inhibitor Phosphate Prodrug

Author

Kephart Susan Elizabeth, Manfred Kraus, Hovhannes J. Gukasyan, Sutton Scott Channing, Joseph H Lee, Zehnder Luke Raymond, Shinji Yamazaki, Pei-Pei Kung, Buwen Huang, and Connie Fan

Subjects
Models, Molecular, Lymphoma, B-Cell, Pyridones, Cell, Antineoplastic Agents, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Mice, Pharmacokinetics, In vivo, Oral administration, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Prodrugs, 030304 developmental biology, 0303 health sciences, Chemistry, EZH2, Prodrug, Phosphate, Combinatorial chemistry, Xenograft Model Antitumor Assays, 0104 chemical sciences, Rats, 010404 medicinal & biomolecular chemistry, medicine.anatomical_structure, Cell culture, Drug Design, Molecular Medicine
Abstract

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.

Published
2021

6. Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer

Author

Freeman-Cook, Kevin D., primary, Hoffman, Robert L., additional, Behenna, Douglas C., additional, Boras, Britton, additional, Carelli, Jordan, additional, Diehl, Wade, additional, Ferre, Rose Ann, additional, He, You-Ai, additional, Hui, Andrea, additional, Huang, Buwen, additional, Huser, Nanni, additional, Jones, Rhys, additional, Kephart, Susan E., additional, Lapek, John, additional, McTigue, Michele, additional, Miller, Nichol, additional, Murray, Brion W., additional, Nagata, Asako, additional, Nguyen, Lisa, additional, Niessen, Sherry, additional, Ninkovic, Sacha, additional, O’Doherty, Inish, additional, Ornelas, Martha A., additional, Solowiej, James, additional, Sutton, Scott C., additional, Tran, Khanh, additional, Tseng, Elaine, additional, Visswanathan, Ravi, additional, Xu, Meirong, additional, Zehnder, Luke, additional, Zhang, Qin, additional, Zhang, Cathy, additional, and Dann, Stephen, additional

Published
2021
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8. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor

Author

Xinmeng Jasmine Mu, Meirong Xu, Shahram Salek-Ardakani, Cinthia Costa-Jones, Lisa Nguyen, James Solowiej, David Looper, Scott L. Weinrich, Robert Louis Hoffman, Sutton Scott Channing, Sacha Ninkovic, Kephart Susan Elizabeth, Sherry Niessen, John Chionis, Jadwiga Bienkowska, Kevin Daniel Freeman-Cook, Rose Ann Ferre, John Lapek, Cecilia Oderup, Jordan Carelli, Cathy Zhang, Nanni Huser, Elizabeth A. McMillan, Asako Nagata, Martha A. Ornelas, Brion W. Murray, Douglas Carl Behenna, Koleen Eisele, Todd VanArsdale, Zhou Zhu, Zhengyan Kan, Chaoting Liu, Nichol Miller, Zehnder Luke Raymond, Michael A. White, Ying Ding, Nathan V. Lee, Jonathan Almaden, Qin Zhang, Tran Khanh Tuan, Ping Wei, Stephen Dann, Britton Boras, Tim S. Wang, Ravi Visswanathan, You-Ai He, Michele McTigue, and Elizabeth Wilson

Subjects
Male, Cancer Research, Cyclin E, Palbociclib, Neoplasms, medicine, Humans, Oncogene, biology, business.industry, Cell Cycle, Cyclin-Dependent Kinase 2, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 4, Cancer, Cyclin-Dependent Kinase 6, Cell cycle, medicine.disease, Immune checkpoint, Oncology, Cancer research, biology.protein, Female, Cyclin-dependent kinase 6, biological phenomena, cell phenomena, and immunity, business
Abstract

Summary The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2− breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.

Published
2021
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9. Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195)

Author

Cheng, Hengmiao, primary, Orr, Suvi T. M., additional, Bailey, Simon, additional, Brooun, Alexei, additional, Chen, Ping, additional, Deal, Judith G., additional, Deng, Yali L., additional, Edwards, Martin P., additional, Gallego, Gary M., additional, Grodsky, Neil, additional, Huang, Buwen, additional, Jalaie, Mehran, additional, Kaiser, Stephen, additional, Kania, Robert S., additional, Kephart, Susan E., additional, Lafontaine, Jennifer, additional, Ornelas, Martha A., additional, Pairish, Mason, additional, Planken, Simon, additional, Shen, Hong, additional, Sutton, Scott, additional, Zehnder, Luke, additional, Almaden, Chau D., additional, Bagrodia, Shubha, additional, Falk, Matthew D., additional, Gukasyan, Hovhannes J., additional, Ho, Caroline, additional, Kang, Xiaolin, additional, Kosa, Rachel E., additional, Liu, Ling, additional, Spilker, Mary E., additional, Timofeevski, Sergei, additional, Visswanathan, Ravi, additional, Wang, Zhenxiong, additional, Meng, Fanxiu, additional, Ren, Shijian, additional, Shao, Li, additional, Xu, Feng, additional, and Kath, John C., additional

Published
2020
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10. A rare acid-promoted elimination of O-methyl oximes: a practical synthesis of 3-cyano-4-benzopyrones

Author

Hsung, Richard P., Zificsak, Craig A., Wei, Lin-Li, Zehnder, Luke R., Park, Francis, Kim, Michelle, and Tran, Thuy-Trang T.

Subjects
Chemistry, Organic -- Research, Amino acids -- Research, Aldehydes -- Research, Biological sciences, Chemistry
Abstract

A synthesis of 3-cyano-4-benzopyrone derivatives by acid-promoted elimination of O-methyl oximes has been reported. The authors examine procedures that describe preparations from the aldehydes through oxime intermediates.

Published
1999

11. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Author

Michael R. Collins, Robert Steven Kania, Connie Fan, Sutton Scott Channing, Dominique Verhelle, Kephart Susan Elizabeth, Martin James Wythes, Shuiwang Wang, Karen A. Maegley, Lisa Nguyen, Daniel Tyler Richter, A.E. Stewart, Pei-Pei Kung, Buwen Huang, Shikhar Sharma, Shinji Yamazaki, Ya-Li Deng, Rita Grantner, Patrick Bingham, Robert Arnold Kumpf, Penney Khamphavong, Jinjiang Zhu, Dac M. Dinh, Manfred Kraus, Wei Liu, Sean Uryu, Jillian E. Spangler, Wenyue Hu, Hui Wang, Robert A. Rollins, Cody Krivacic, Zehnder Luke Raymond, Neal W. Sach, Alexei Brooun, John Sherrill, Shijian Ren, Martin A. Edwards, Huichun Zhu, Ketan S. Gajiwala, Shuibo Xin, and Hovhannes J. Gukasyan

Subjects
0301 basic medicine, Chemistry, Stereochemistry, Ligand (biochemistry), 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, In vivo, Drug Discovery, Lactam, Molecular Medicine, Moiety, Molecule, Solubility, Lead compound, ADME
Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-pr...

Published
2017
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12. Synthesis of oxetane-3-carboxaldehyde and methyl oxetane-3-carboxylate via homologation of oxetane-3-one

Author

Zehnder Luke Raymond, Sutton Scott Channing, Kephart Susan Elizabeth, and Buwen Huang

Subjects
Allylic rearrangement, 010405 organic chemistry, Chemistry, Organic Chemistry, 010402 general chemistry, Ring (chemistry), Oxetane, 01 natural sciences, Biochemistry, 0104 chemical sciences, chemistry.chemical_compound, Dihydroxylation, Hydrogenolysis, Drug Discovery, Organic chemistry, Carboxylate, Oxidative cleavage
Abstract

A 4-pot telescoped procedure to prepare oxetane-3-carboxaldehyde and methyl oxetane-3-carboxylate was developed using readily available starting materials. Classical homologation methods applied to oxetane-3-one proved challenging due to the sensitivity of the oxetane ring toward strongly oxidative, basic and acidic conditions. Subsequently, a mild homologation sequence was developed. The key steps involve a Tsuji hydrogenolysis of an allylic acetate, osmium-free dihydroxylation and oxidative cleavage. Although methyl oxetane-3-carboxylate is marketed by a small number of specialty chemical companies, this work represents the first published preparation of this vital building block.

Published
2016
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14. SAH derived potent and selective EZH2 inhibitors

Author

Patrick Bingham, Wade Diehl, Karen A. Maegley, Cody Krivacic, Buwen Huang, Zehnder Luke Raymond, Xiu Yu, Pei-Pei Kung, Tatlock John H, and Ketan S. Gajiwala

Subjects
Models, Molecular, Methyltransferase, Clinical Biochemistry, Lysine, Pharmaceutical Science, macromolecular substances, Biochemistry, Structure-Activity Relationship, Drug Discovery, Humans, Enhancer of Zeste Homolog 2 Protein, Molecular Biology, IC50, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, EZH2, Polycomb Repressive Complex 2, Methylation, S-Adenosylhomocysteine, Molecular biology, Lipophilic efficiency, Drug Design, Histone methyltransferase, Molecular Medicine, Nucleoside
Abstract

A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50's against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH.

Published
2015
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15. One-Pot, Metal- and Azide-Free Synthesis of 1,2,3-Triazoles from α-Ketoacetals and Amines.

Author

Zehnder, Luke R., Hawkins, Joel M., and Sutton, Scott C.

Subjects
*AMINES, *FUNCTIONAL groups, *ESTERS, *METALS, *AZIDES
Abstract

An efficient one-pot two-step synthesis of 1,4-disubstituted 1,2,3-triazoles from α-ketoacetals and amines is presented. The method does not use metals, azides, or oxidants, and is compatible with a variety of functional groups, including heterocycles, esters, nitriles, and carbamates. [ABSTRACT FROM AUTHOR]

Published
2020
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16. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Author

Hovhannes J. Gukasyan, Michael R. Collins, Sutton Scott Channing, Kephart Susan Elizabeth, Shinji Yamazaki, Sacha Ninkovic, Simon Bergqvist, Fen Wang, Robert Arnold Kumpf, Michael Ryskin, Patrick Bingham, Pei-Pei Kung, Dominique Verhelle, Brian Yip, Karen A. Maegley, Robert A. Rollins, Peter A. Wells, Martha A. Ornelas, Buwen Huang, Valeria Fantin, Xiu Yu, Stephanie Scales, Wade Diehl, Indrawan James Mcalpine, Cody Krivacic, Mei Cui, Lisa Nguyen, Wenyue Hu, Tatlock John H, Dac M. Dinh, Martin James Wythes, Connie Fan, Gary Li, Martin Paul Edwards, Rui Eugene Yuanjin, John F. Braganza, Zehnder Luke Raymond, and Wei-Guo Zhang

Subjects
0301 basic medicine, Models, Molecular, Lactams, Stereochemistry, Pyridones, Antineoplastic Agents, Mice, SCID, 03 medical and health sciences, chemistry.chemical_compound, Mice, In vivo, Amide, Cell Line, Tumor, Neoplasms, Drug Discovery, Potency, Moiety, Animals, Humans, Enhancer of Zeste Homolog 2 Protein, Ligand efficiency, Isoquinolines, 030104 developmental biology, chemistry, Lipophilic efficiency, Cyclization, Drug Design, Lactam, Molecular Medicine, Female, Linker
Abstract

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

Published
2016

17. ChemInform Abstract: Synthesis of Oxetane-3-carboxaldehyde and Methyl Oxetane-3-carboxylate via Homologation of Oxetane-3-one

Author

Kephart Susan Elizabeth, Sutton Scott Channing, Zehnder Luke Raymond, and Buwen Huang

Subjects
chemistry.chemical_compound, Allylic rearrangement, chemistry, Dihydroxylation, Hydrogenolysis, General Medicine, Carboxylate, Oxetane, Oxidative cleavage, Ring (chemistry), Combinatorial chemistry
Abstract

A 4-pot telescoped procedure to prepare oxetane-3-carboxaldehyde and methyl oxetane-3-carboxylate was developed using readily available starting materials. Classical homologation methods applied to oxetane-3-one proved challenging due to the sensitivity of the oxetane ring toward strongly oxidative, basic and acidic conditions. Subsequently, a mild homologation sequence was developed. The key steps involve a Tsuji hydrogenolysis of an allylic acetate, osmium-free dihydroxylation and oxidative cleavage. Although methyl oxetane-3-carboxylate is marketed by a small number of specialty chemical companies, this work represents the first published preparation of this vital building block.

Published
2016
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18. Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195)

Author

Cheng, Hengmiao, Orr, Suvi T. M., Bailey, Simon, Brooun, Alexei, Chen, Ping, Deal, Judith G., Deng, Yali L., Edwards, Martin P., Gallego, Gary M., Grodsky, Neil, Huang, Buwen, Jalaie, Mehran, Kaiser, Stephen, Kania, Robert S., Kephart, Susan E., Lafontaine, Jennifer, Ornelas, Martha A., Pairish, Mason, Planken, Simon, Shen, Hong, Sutton, Scott, Zehnder, Luke, Almaden, Chau D., Bagrodia, Shubha, Falk, Matthew D., Gukasyan, Hovhannes J., Ho, Caroline, Kang, Xiaolin, Kosa, Rachel E., Liu, Ling, Spilker, Mary E., Timofeevski, Sergei, Visswanathan, Ravi, Wang, Zhenxiong, Meng, Fanxiu, Ren, Shijian, Shao, Li, Xu, Feng, and Kath, John C.

Abstract

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1)(PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.

Published
2021
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20. Optimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-Containing Inhibitors of Heat Shock Protein 90. Identification of Development Candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

Author

Tanya Michelle Jewell, Robert Steven Kania, Anand Sistla, Bennett Michael John, Michael R. Gehring, Evan Smith, Zehnder Luke Raymond, Shinji Yamazaki, Karen A. Maegley, Elena Z. Dovalsantos, Ben Burke, Fen Wang, Sacha Ninkovic, Jeff Wang, Joe Zhongxiang Zhou, Pei-Pei Kung, Min-Jean Yin, Michael J. Hickey, Martin James Wythes, Jerry Meng, Buwen Huang, Ping Kang, John F. Braganza, Ketan S. Gajiwala, Tatlock John H, and Pramod P. Mehta

Subjects
Pyrimidine, biology, Chemistry, Stereochemistry, medicine.drug_class, Carboxamide, Metabolic stability, Combinatorial chemistry, Hsp90, Bioavailability, chemistry.chemical_compound, Heat shock protein, Drug Discovery, Alkoxy group, biology.protein, medicine, Molecular Medicine, Potency
Abstract

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

Published
2011
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21. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Author

Kung, Pei-Pei, primary, Bingham, Patrick, additional, Brooun, Alexei, additional, Collins, Michael, additional, Deng, Ya-Li, additional, Dinh, Dac, additional, Fan, Connie, additional, Gajiwala, Ketan S., additional, Grantner, Rita, additional, Gukasyan, Hovhannes J., additional, Hu, Wenyue, additional, Huang, Buwen, additional, Kania, Robert, additional, Kephart, Susan E., additional, Krivacic, Cody, additional, Kumpf, Robert A., additional, Khamphavong, Penney, additional, Kraus, Manfred, additional, Liu, Wei, additional, Maegley, Karen A., additional, Nguyen, Lisa, additional, Ren, Shijian, additional, Richter, Dan, additional, Rollins, Robert A., additional, Sach, Neal, additional, Sharma, Shikhar, additional, Sherrill, John, additional, Spangler, Jillian, additional, Stewart, Albert E., additional, Sutton, Scott, additional, Uryu, Sean, additional, Verhelle, Dominique, additional, Wang, Hui, additional, Wang, Shuiwang, additional, Wythes, Martin, additional, Xin, Shuibo, additional, Yamazaki, Shinji, additional, Zhu, Huichun, additional, Zhu, JinJiang, additional, Zehnder, Luke, additional, and Edwards, Martin, additional

Published
2017
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22. A formal [3+3] cycloaddition reaction. Improved reactivity using alpha,beta-unsaturated iminium salts and evidence for reversibility of 6pi-electron electrocyclic ring closure of 1-oxatrienes

Author

Shen, Hong C., Wang, Jiashi, Cole, Kevin P., McLaughlin, Michael J., Morgan, Christopher D., Douglas, Christopher J., Hsung, Richard P., Coverdale, Heather A., Gerasyuto, Aleksey I., Hahn, Juliet M., Liu, Jia, Sklenicka, Heather M., Wei, Lin-Li, Zehnder, Luke R., and Zificsak, Craig A.

Subjects
Chemistry, Organic -- Research, Ring formation (Chemistry), Reactivity (Chemistry) -- Analysis, Salts -- Composition, Biological sciences, Chemistry
Abstract

Research has been conducted on [3+3] cycloaddition reaction . The description of this reaction carried out via the use of 4-hydroxy-2-pyrones and 1,3-diketones is presented.

Published
2003

23. Design, synthesis, and biological evaluation of novel human 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP) substrates

Author

Skalitzky Donald James, Karen A. Maegley, Stanley William Kupchinsky, Pei Pei Kung, Anne Ekker, Laura Anne Bloom, Leslie A. Kuhn, Peter W. Rose, Jerry J. Meng, Zehnder Luke Raymond, and M. Catherine Johnson

Subjects
chemistry.chemical_classification, 5'-deoxy-5'-methylthioadenosine phosphorylase, Molecular Structure, biology, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Substrate (chemistry), Biochemistry, Chemical synthesis, In vitro, Substrate Specificity, Enzyme, Purine-Nucleoside Phosphorylase, chemistry, Design synthesis, Drug Design, Drug Discovery, Glycosyltransferase, biology.protein, Humans, Molecular Medicine, Molecular Biology, Biological evaluation
Abstract

The structure-based design, chemical synthesis, and biological evaluation of novel MTAP substrates are described. These compounds incorporate various C5′-moieties and are shown to have different k cat / K m values compared with the natural MTAP substrate (MTA).

Published
2005
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24. Optimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-Containing Inhibitors of Heat Shock Protein 90. Identification of Development Candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

Author

Zehnder, Luke, Bennett, Michael, Meng, Jerry, Huang, Buwen, Ninkovic, Sacha, Wang, Fen, Braganza, John, Tatlock, John, Jewell, Tanya, Zhou, Joe Zhongxiang, Burke, Ben, Wang, Jeff, Maegley, Karen, Mehta, Pramod P., Yin, Min-Jean, Gajiwala, Ketan S., Hickey, Michael J., Yamazaki, Shinji, Smith, Evan, Kang, Ping, Sistla, Anand, Dovalsantos, Elena, Gehring, Michael R., Kania, Robert, Wythes, Martin, and Kung, Pei-Pei

Abstract

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

Published
2024
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25. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Author

Kung, Pei-Pei, Bingham, Patrick, Brooun, Alexei, Collins, Michael, Deng, Ya-Li, Dinh, Dac, Fan, Connie, Gajiwala, Ketan S., Grantner, Rita, Gukasyan, Hovhannes J., Hu, Wenyue, Huang, Buwen, Kania, Robert, Kephart, Susan E., Krivacic, Cody, Kumpf, Robert A., Khamphavong, Penney, Kraus, Manfred, Liu, Wei, Maegley, Karen A., Nguyen, Lisa, Ren, Shijian, Richter, Dan, Rollins, Robert A., Sach, Neal, Sharma, Shikhar, Sherrill, John, Spangler, Jillian, Stewart, Albert E., Sutton, Scott, Uryu, Sean, Verhelle, Dominique, Wang, Hui, Wang, Shuiwang, Wythes, Martin, Xin, Shuibo, Yamazaki, Shinji, Zhu, Huichun, Zhu, JinJiang, Zehnder, Luke, and Edwards, Martin

Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D(clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23aexhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23ain complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Published
2024
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26. Correction to Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Author

Kung, Pei-Pei, primary, Rui, Eugene, additional, Bergqvist, Simon, additional, Bingham, Patrick, additional, Braganza, John, additional, Collins, Michael, additional, Cui, Mei, additional, Diehl, Wade, additional, Dinh, Dac, additional, Fan, Connie, additional, Fantin, Valeria R., additional, Gukasyan, Hovhannes J., additional, Hu, Wenyue, additional, Huang, Buwen, additional, Kephart, Susan, additional, Krivacic, Cody, additional, Kumpf, Robert A., additional, Li, Gary, additional, Maegley, Karen A., additional, McAlpine, Indrawan, additional, Nguyen, Lisa, additional, Ninkovic, Sacha, additional, Ornelas, Martha, additional, Ryskin, Michael, additional, Scales, Stephanie, additional, Sutton, Scott, additional, Tatlock, John, additional, Verhelle, Dominique, additional, Wang, Fen, additional, Wells, Peter, additional, Wythes, Martin, additional, Yamazaki, Shinji, additional, Yip, Brian, additional, Yu, Xiu, additional, Zehnder, Luke, additional, Zhang, Wei-Guo, additional, Rollins, Robert A., additional, and Edwards, Martin, additional

Published
2016
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27. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

Author

Kung, Pei-Pei, primary, Rui, Eugene, additional, Bergqvist, Simon, additional, Bingham, Patrick, additional, Braganza, John, additional, Collins, Michael, additional, Cui, Mei, additional, Diehl, Wade, additional, Dinh, Dac, additional, Fan, Connie, additional, Fantin, Valeria R., additional, Gukasyan, Hovhannes J., additional, Hu, Wenyue, additional, Huang, Buwen, additional, Kephart, Susan, additional, Krivacic, Cody, additional, Kumpf, Robert A., additional, Li, Gary, additional, Maegley, Karen A., additional, McAlpine, Indrawan, additional, Nguyen, Lisa, additional, Ninkovic, Sacha, additional, Ornelas, Martha, additional, Ryskin, Michael, additional, Scales, Stephanie, additional, Sutton, Scott, additional, Tatlock, John, additional, Verhelle, Dominique, additional, Wang, Fen, additional, Wells, Peter, additional, Wythes, Martin, additional, Yamazaki, Shinji, additional, Yip, Brian, additional, Yu, Xiu, additional, Zehnder, Luke, additional, Zhang, Wei-Guo, additional, Rollins, Robert A., additional, and Edwards, Martin, additional

Published
2016
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28. Pyridine-3-propanoic acids: Discovery of dual PPARalpha/gamma agonists as antidiabetic agents

Author

Mary Hess, Simon Bailey, Christie Lance Christopher, Jack H. Kellum, Brett H. Simmons, Guy A. McClellan, Paul S. Humphries, Kathleen M. Ogilvie, Jonathon V. Almaden, Skalitzky Donald James, Young Ha Kim, Shaoxian Sun, Thomas J. Carlson, David M. Wilhite, James D. Fraser, Zehnder Luke Raymond, Sandra J. Barnum, and Quyen-Quyen T. Do

Subjects
Agonist, Gene isoform, Blood Glucose, medicine.drug_class, Stereochemistry, Pyridines, Carboxylic acid, Clinical Biochemistry, Pharmaceutical Science, Peroxisome proliferator-activated receptor, Biochemistry, Chemical synthesis, Ether, Mice, Structure-Activity Relationship, In vivo, Cell Line, Tumor, Drug Discovery, medicine, Diabetes Mellitus, Animals, Humans, Hypoglycemic Agents, PPAR alpha, Molecular Biology, chemistry.chemical_classification, Molecular Structure, Organic Chemistry, Body Weight, In vitro, PPAR gamma, chemistry, Molecular Medicine, Thiazolidinediones, Selectivity
Abstract

A series of novel pyridine-3-propanoic acids was synthesized. A structure–activity relationship study of these compounds led to the identification of potent dual PPARα/γ agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.

Published
2006

29. Optimization of Potent, Selective, and Orally Bioavailable Pyrrolodinopyrimidine-Containing Inhibitors of Heat Shock Protein 90. Identification of Development Candidate 2-Amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

Author

Zehnder, Luke, primary, Bennett, Michael, additional, Meng, Jerry, additional, Huang, Buwen, additional, Ninkovic, Sacha, additional, Wang, Fen, additional, Braganza, John, additional, Tatlock, John, additional, Jewell, Tanya, additional, Zhou, Joe Zhongxiang, additional, Burke, Ben, additional, Wang, Jeff, additional, Maegley, Karen, additional, Mehta, Pramod P., additional, Yin, Min-Jean, additional, Gajiwala, Ketan S., additional, Hickey, Michael J., additional, Yamazaki, Shinji, additional, Smith, Evan, additional, Kang, Ping, additional, Sistla, Anand, additional, Dovalsantos, Elena, additional, Gehring, Michael R., additional, Kania, Robert, additional, Wythes, Martin, additional, and Kung, Pei-Pei, additional

Published
2011
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31. ChemInform Abstract: Stereoselective trans- and cis-Dihydroxylations of 2H-Pyranyl and Dihydropyridinyl Heterocycles Synthesized from Formal [3 + 3]-Cycloaddition Reactions of α,β-Unsaturated Iminium Ions with 1,3-Dicarbonyl Equivalents.

Author

Zehnder, Luke R., primary, Wei, Lin-Li, additional, Hsung, Richard P., additional, Cole, Kevin P., additional, McLaughlin, Michael J., additional, Shen, Hong C., additional, Sklenicka, Heather M., additional, Wang, Jiashi, additional, and Zificsak, Craig A., additional

Published
2010
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32. Pyridine-3-propanoic acids: Discovery of dual PPARα/γ agonists as antidiabetic agents

Author

Humphries, Paul S., primary, Bailey, Simon, additional, Almaden, Jonathon V., additional, Barnum, Sandra J., additional, Carlson, Thomas J., additional, Christie, Lance C., additional, Do, Quyen-Quyen T., additional, Fraser, James D., additional, Hess, Mary, additional, Kellum, Jack, additional, Kim, Young H., additional, McClellan, Guy A., additional, Ogilvie, Kathleen M., additional, Simmons, Brett H., additional, Skalitzky, Donald, additional, Sun, Shaoxian, additional, Wilhite, David, additional, and Zehnder, Luke R., additional

Published
2006
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33. Design, synthesis, and biological evaluation of novel human 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP) substrates

Author

Kung, Pei-Pei, primary, Zehnder, Luke R., additional, Meng, Jerry J., additional, Kupchinsky, Stanley W., additional, Skalitzky, Donald J., additional, Johnson, M. Catherine, additional, Maegley, Karen A., additional, Ekker, Anne, additional, Kuhn, Leslie A., additional, Rose, Peter W., additional, and Bloom, Laura A., additional

Published
2005
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36. A Formal [3 + 3] Cycloaddition Reaction. Improved Reactivity Using α,β-Unsaturated Iminium Salts and Evidence for Reversibility of 6π-Electron Electrocyclic Ring Closure of 1-Oxatrienes

Author

Shen, Hong C., primary, Wang, Jiashi, additional, Cole, Kevin P., additional, McLaughlin, Michael J., additional, Morgan, Christopher D., additional, Douglas, Christopher J., additional, Hsung, Richard P., additional, Coverdale, Heather A., additional, Gerasyuto, Aleksey I., additional, Hahn, Juliet M., additional, Liu, Jia, additional, Sklenicka, Heather M., additional, Wei, Lin-Li, additional, Zehnder, Luke R., additional, and Zificsak, Craig A., additional

Published
2003
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39. Stereoselective trans- and cis-Dihydroxylations of 2H-Pyranyl and Dihydropyridinyl Heterocycles Synthesized from Formal [3 + 3]-Cycloaddition Reactions of α,β-Unsaturated Iminium Ions with 1,3-Dicarbonyl Equivalents†

Author

Zehnder, Luke R., primary, Wei, Lin-Li, additional, Hsung, Richard P., additional, Cole, Kevin P., additional, McLaughlin, Michael J., additional, Shen, Hong C., additional, Sklenicka, Heather M., additional, Wang, Jiashi, additional, and Zificsak, Craig A., additional

Published
2001
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47. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

Author

Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania R, Kephart SE, Krivacic C, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter D, Rollins RA, Sach N, Sharma S, Sherrill J, Spangler J, Stewart AE, Sutton S, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, and Edwards M

Subjects
Administration, Oral, Biological Availability, Cell Line, Tumor, Humans, Isoquinolines administration & dosage, Isoquinolines chemistry, Models, Molecular, Molecular Conformation, Drug Design, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Isoquinolines pharmacokinetics, Isoquinolines pharmacology
Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp 3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Published
2018
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48. A formal [3 + 3] cycloaddition reaction. Improved reactivity using alpha,beta-unsaturated iminium salts and evidence for reversibility of 6pi-electron electrocyclic ring closure of 1-oxatrienes.

Author

Shen HC, Wang J, Cole KP, McLaughlin MJ, Morgan CD, Douglas CJ, Hsung RP, Coverdale HA, Gerasyuto AI, Hahn JM, Liu J, Sklenicka HM, Wei LL, Zehnder LR, and Zificsak CA

Subjects
Alkenes chemistry, Catalysis, Crystallography, X-Ray, Cyclization, Imines chemistry, Indicators and Reagents, Magnetic Resonance Spectroscopy, Molecular Structure, Oxidation-Reduction, Salts chemical synthesis, Stereoisomerism, Chemistry, Organic methods, Ketones chemistry, Pyrans chemical synthesis, Pyrones chemistry
Abstract

A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.

Published
2003
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