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Your search keyword '"allosteric inhibitor"' showing total 7 results
Start Over Descriptor "allosteric inhibitor" Publisher escholarship, university of california
7 results on '"allosteric inhibitor"'

1. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers

Author

Campbell, Marcia R, Ruiz-Saenz, Ana, Peterson, Elliott, Agnew, Christopher, Ayaz, Pelin, Garfinkle, Sam, Littlefield, Peter, Steri, Veronica, Oeffinger, Julie, Sampang, Maryjo, Shan, Yibing, Shaw, David E, Jura, Natalia, and Moasser, Mark M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Aniline Compounds, Breast Neoplasms, Carcinogenesis, Cell Line, Tumor, Female, Humans, Nitriles, Quinolines, Receptor, ErbB-2, Receptor, ErbB-3, Signal Transduction, Receptor, erbB-2, Receptor, erbB-3, AP-2 pocket, ERBB2, ERBB3, HER2, HER3, allosteric inhibitor, bosutinib, breast cancer, Medical Physiology, Biological sciences
Abstract

Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.

Published
2022

2. Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98

Author

Shao, Hao and Gestwicki, Jason E

Subjects
Medicinal and Biomolecular Chemistry, Organic Chemistry, Chemical Sciences, Cancer, Aging, Breast Cancer, Antineoplastic Agents, Benzothiazoles, Binding Sites, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Fluorescent Dyes, HSP70 Heat-Shock Proteins, Humans, Molecular Docking Simulation, Molecular Structure, Protein Binding, Structure-Activity Relationship, Allosteric inhibitor, Molecular chaperone, Proteostasis, Prostate cancer, Breast cancer, Chemical probe, Anti-cancer agents, Fluorescence, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70, showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 µM) in breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.

Published
2020

3. Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

Author

LaPorte, Matthew G, Burnett, James C, Colombo, Raffaele, Bulfer, Stacie L, Alverez, Celeste, Chou, Tsui-Fen, Neitz, R Jeffrey, Green, Neal, Moore, William J, Yue, Zhizhou, Li, Shan, Arkin, Michelle R, Wipf, Peter, and Huryn, Donna M

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Biotechnology, AAA plus ATPase, p97, allosteric inhibitor, protein homeostasis modulator, anticancer, phenyl indole, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.

Published
2018

4. Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Author

Alverez, Celeste, Bulfer, Stacie L, Chakrasali, Ramappa, Chimenti, Michael S, Deshaies, Raymond J, Green, Neal, Kelly, Mark, LaPorte, Matthew G, Lewis, Taber S, Liang, Mary, Moore, William J, Neitz, R Jeffrey, Peshkov, Vsevolod A, Walters, Michael A, Zhang, Feng, Arkin, Michelle R, Wipf, Peter, and Huryn, Donna M

Subjects
Prevention, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, AAA ATPase, p97 inhibitor, allosteric inhibitor, indole amide, protein homeostasis, ubiquitin pathway modulator, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences
Abstract

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts.

Published
2016

5. Toward the Development of Allosteric Inhibitors of IKK2

Author

Hotchkiss, Sonjiala Jackson

Subjects
Biochemistry, allosteric Inhibitor, drug development, HDX, IKK, IKK2, NF-κB
Abstract

IκB kinase (IKK) is the essential kinase in the activation pathway of NF-κB, a family of transcription factors active in both innate and adaptive immunity. IKK has two catalytic subunits, IKK1 and IKK2, and one scaffolding subunit NEMO. As aberrant activation of NF-κB is a factor in many diseases including cancer and inflammatory disorders, research has been directed toward developing inhibitors to its activation. Most developed inhibitors target IKK2 and work as ATP competitors. However, ATP competitive inhibitors are often too nonspecific and have too many adverse side effects to be developed as effective drug treatments. I tested and characterized the function of small molecule allosteric inhibitors identified by our lab named #65.5, #65.5.2, and #65.5.3. Allosteric inhibitors of IKK2 are expected to result in greater specificity with fewer adverse side effects. I used cell-based assays, kinase experiments, HDXMS, and MS-MS to confirm that our inhibitors prevented NF-κB activation, worked as allosteric inhibitors, and bound to the pocket predicted by virtual screening. Based on analysis of the collected data, we developed a model for how our inhibitors work to prevent IKK2 activation.

Published
2018

6. Development of Allosteric Inhibitors Targeting Human Herpesviral Proteases

Author

Shahian, Tina

Subjects
Biochemistry, Virology, Allosteric inhibitor, alpha helix mimetic, dimer disruptor, Herpesvirus protease, High throughput screening, Kaposi's Sarcoma-Associated Herpesvirus
Abstract

Human herpesviruses (HHVs) make up one of the most prevalent viral families and are the etiological agents of a variety of devastating human illnesses that lack safe and effective treatments. All HHVs express a dimeric serine protease that is essential to the viral life cycle. Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr), a gamma subfamily member, was chosen as the model system for developing broad-spectrum herpesviral inhibitors. Of particular interest are KSHV Pr inhibitors that act allosterically, either by dimer dissociation or other mechanisms. A small-molecule KSHV Pr inhibitor has been identified that traps a transient allosteric pocket at the protease dimer interface. The binding of this molecule (DD2) has been shown to prevent the dimerization of KSHV Pr, which is required for its activation. This novel binding pocket is bioinformatically predicted to be conserved across all HHV proteases and DD2 has been shown to have activity against the serine protease from cytolomegalovirus (CMV) a member of the beta herpesvirus subfamily. Additionally, methodologies have been developed to identify new inhibitors via a high throughput screen, elucidate the mechanism and binding modes of screening hits, and test for efficacy in a cell culture viral replication assay. This work presents methodologies and demonstrates the feasibility for identifying and using small-molecule allosteric inhibitors to target a conserved enzyme family that is conserved across a viral family.

Published
2011

7. Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Author

Matthew G. LaPorte, R. Jeffrey Neitz, Mary Liang, Taber S. Lewis, Feng Zhang, Peter Wipf, Neal Jeffrey Green, Michelle R. Arkin, Vsevolod A. Peshkov, Mark J. S. Kelly, Michael S. Chimenti, Ramappa Chakrasali, William J. Moore, Celeste Alverez, Michael A. Walters, Stacie L. Bulfer, Donna M. Huryn, and Raymond J. Deshaies

Subjects
0301 basic medicine, P97 ATPase, p97 inhibitor, Stereochemistry, Allosteric regulation, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Medicinal and Biomolecular Chemistry, Ubiquitin, Amide, Drug Discovery, indole amide, AAA ATPase, Indole test, protein homeostasis, allosteric inhibitor, biology, Chemistry, Drug discovery, Prevention, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, AAA proteins, 030104 developmental biology, 5.1 Pharmaceuticals, biology.protein, ubiquitin pathway modulator, Development of treatments and therapeutic interventions, Uncompetitive inhibitor
Abstract

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts.

Published
2016

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