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5 results on '"Laszlo, Jimmy"'

1. 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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2. The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors

Author

Wurz, Ryan P., Pettus, Liping H., Jackson, Claire, Wu, Bin, Wang, Hui-Ling, Herberich, Brad, Cee, Victor, Lanman, Brian A., Reed, Anthony B., Chavez, Frank, Jr., Nixey, Thomas, Laszlo, Jimmy, III, Wang, Paul, Nguyen, Yen, Sastri, Christine, Guerrero, Nadia, Winston, Jeff, Lipford, J. Russell, Lee, Matthew R., Andrews, Kristin L., Mohr, Christopher, Xu, Yang, Zhou, Yihong, Reid, Darren L., and Tasker, Andrew S.

Published
2015
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3. 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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4. Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors

Author

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

Published
2016
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5. 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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