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Article ; Online: Sulforaphane is Synergistic with CB-5083 and Inhibits Colony Formation of CB-5083-Resistant HCT116 Cells.

Wang, Feng / Li, Shan / Rosencrans, William M / Cheng, Kai-Wen / Stott, Gordon M / Mroczkowski, Barbara / Chou, Tsui-Fen

ChemMedChem

2022 Volume 17, Issue 11, Page(s) e202200030

Abstract: Human p97 is a potential drug target in oncology. Mutation-driven drug resistance is an obstacle to the long-term efficacy of targeted therapy. We found that the ATPase activity for one of the CB-5083-resistant p97 mutants was reduced, which also ... ...

Abstract	Human p97 is a potential drug target in oncology. Mutation-driven drug resistance is an obstacle to the long-term efficacy of targeted therapy. We found that the ATPase activity for one of the CB-5083-resistant p97 mutants was reduced, which also attenuated the degradation of K48 ubiquitinated proteins in cells. To understand how p97 mutant cells with significantly reduced ATPase activity can still grow, we discovered reduced levels of CHOP and NF-κB activation in the p97 mutant cells and these cellular changes can potentially protect HCT116 cells from death due to lowered p97 activity. In addition, the NF-kB inhibitor Sulforaphane reduces proliferation of CB-5083 resistant cells and acts synergistically with CB-5083 to block proliferation of the parental HCT116 cells. The combination of Sulforaphane and CB-5083 may be a useful treatment strategy to combat CB-5083 resistance.
MeSH term(s)	Adenosine Triphosphatases ; HCT116 Cells ; Humans ; Indoles/pharmacology ; Isothiocyanates ; Pyrimidines ; Sulfoxides ; Valosin Containing Protein/metabolism
Chemical Substances	CB-5083 ; Indoles ; Isothiocyanates ; Pyrimidines ; Sulfoxides ; Adenosine Triphosphatases (EC 3.6.1.-) ; Valosin Containing Protein (EC 3.6.4.6) ; sulforaphane (GA49J4310U)
Language	English
Publishing date	2022-04-22
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202200030
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Article ; Online: Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy.

Wang, Feng / Li, Shan / Gan, Taiping / Stott, Gordon M / Flint, Andrew / Chou, Tsui-Fen

ChemMedChem

2020 Volume 15, Issue 8, Page(s) 685–694

Abstract: A major challenge of targeted cancer therapy is the selection for drug-resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its ... ...

Abstract	A major challenge of targeted cancer therapy is the selection for drug-resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its vital role in cell growth and survival. One ATP-competitive p97 inhibitor, CB-5083, has entered clinical trials. Selective pressure on HCT116 cells dosed with CB-5083 identified five different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB-5083 resistant p97 mutants, N660 K and T688 A, were also resistant to several other ATP-competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS-873 and UPCDC-30245 were unaffected by these mutations. We also established a CB-5083 resistant cell line that harbors a new p97 double mutation (D649 A/T688 A). While CB-5083, NMS-873, and UPCDC-30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS-873 and UPCDC-30245 were 30-fold more potent in inhibiting the CB-5083 resistant D649 A/T688 A double mutant than CB-5083. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP-competitive p97 inhibitors arises during anticancer treatment.
MeSH term(s)	Acetanilides/chemistry ; Acetanilides/pharmacology ; Adenosine Triphosphatases/antagonists & inhibitors ; Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Allosteric Regulation/drug effects ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Benzothiazoles/chemistry ; Benzothiazoles/pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/drug effects ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HCT116 Cells ; Humans ; Indoles/chemistry ; Indoles/pharmacology ; Models, Molecular ; Molecular Structure ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Pyrimidines/chemistry ; Pyrimidines/pharmacology
Chemical Substances	Acetanilides ; Antineoplastic Agents ; Benzothiazoles ; CB-5083 ; Enzyme Inhibitors ; Indoles ; NMS-873 ; Nuclear Proteins ; Pyrimidines ; Adenosine Triphosphate (8L70Q75FXE) ; Adenosine Triphosphatases (EC 3.6.1.-) ; p97 ATPase (EC 3.6.1.-)
Language	English
Publishing date	2020-03-23
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.201900722
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Article ; Online: Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid.

Frank, Anderson R / Li, Vicky / Shelton, Spencer D / Kim, Jiwoong / Stott, Gordon M / Neckers, Leonard M / Xie, Yang / Williams, Noelle S / Mishra, Prashant / McFadden, David G

Cancer discovery

2023 Volume 13, Issue 8, Page(s) 1884–1903

Abstract: A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial ... ...

Abstract	A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration. Significance: HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749.
MeSH term(s)	Humans ; Fermentation ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/pathology ; Adenoma, Oxyphilic/genetics ; DNA, Mitochondrial/genetics ; Adenocarcinoma ; Carcinoma
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-22-0982
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Article ; Online: Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.

Teuscher, Kevin B / Mills, Jonathan J / Tian, Jianhua / Han, Changho / Meyers, Kenneth M / Sai, Jiqing / South, Taylor M / Crow, Mackenzie M / Van Meveren, Mayme / Sensintaffar, John L / Zhao, Bin / Amporndanai, Kangsa / Moore, William J / Stott, Gordon M / Tansey, William P / Lee, Taekyu / Fesik, Stephen W

Journal of medicinal chemistry

2023 Volume 66, Issue 24, Page(s) 16783–16806

Abstract: The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against ... ...

Abstract	The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[
MeSH term(s)	Animals ; WD40 Repeats ; Drug Discovery ; Antineoplastic Agents/pharmacology
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01529
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Article ; Online: Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.

Teuscher, Kevin B / Meyers, Kenneth M / Wei, Qiangqiang / Mills, Jonathan J / Tian, Jianhua / Alvarado, Joseph / Sai, Jiqing / Van Meveren, Mayme / South, Taylor M / Rietz, Tyson A / Zhao, Bin / Moore, William J / Stott, Gordon M / Tansey, William P / Lee, Taekyu / Fesik, Stephen W

Journal of medicinal chemistry

2022 Volume 65, Issue 8, Page(s) 6287–6312

Abstract: WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization ...

Abstract	WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new
MeSH term(s)	Humans ; Intracellular Signaling Peptides and Proteins ; WD40 Repeats
Chemical Substances	Intracellular Signaling Peptides and Proteins ; WDR5 protein, human
Language	English
Publishing date	2022-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c00195
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Article: Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer.

ACS medicinal chemistry letters

2023 Volume 14, Issue 7, Page(s) 977–985

Abstract: The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, ...

Abstract	The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.3c00163
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Article ; Online: Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models.

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 120, Issue 1, Page(s) e2211297120

Abstract: WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to ...

Abstract	WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P
MeSH term(s)	Animals ; Humans ; Mice ; Chromatin ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; Models, Animal ; WD40 Repeats ; Neoplasms/drug therapy ; Cell Line, Tumor
Chemical Substances	Chromatin ; Intracellular Signaling Peptides and Proteins ; WDR5 protein, human
Language	English
Publishing date	2022-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2211297120
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Article ; Online: Comparative Oncology Assessment of a Novel Inhibitor of Valosin-Containing Protein in Tumor-Bearing Dogs.

LeBlanc, Amy K / Mazcko, Christina N / Fan, Timothy M / Vail, David M / Flesner, Brian K / Bryan, Jeffrey N / Li, Shan / Wang, Feng / Harris, Scott / Vargas, Jesse D / Govindharajulu, Jeevan P / Jaganathan, Soumya / Tomaino, Francesca / Srivastava, Apurva K / Chou, Tsui-Fen / Stott, Gordon M / Covey, Joseph M / Mroczkowski, Barbara / Doroshow, James H

Molecular cancer therapeutics

2022 Volume 21, Issue 10, Page(s) 1510–1523

Abstract: Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of ... ...

Abstract	Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types assessed included solid malignancies, lymphomas, and multiple myeloma. Through a stepwise dose and schedule escalation schema, we determined the maximum tolerated dose to be 7.5 mg/kg when administered orally on a 4 days on, 3 days off schedule per week for 3 consecutive weeks. Adverse events were minimal and mainly related to the gastrointestinal system. Pharmacokinetic/pharmacodynamic data suggest a relationship between exposure and modulation of targets related to induction of the unfolded protein response, but not to tolerability of the agent. An efficacy signal was detected in 33% (2/6) of dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Dogs ; Enzyme Inhibitors/therapeutic use ; Lymphoma/drug therapy ; Lymphoma/pathology ; Lymphoma/veterinary ; Maximum Tolerated Dose ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Multiple Myeloma/veterinary ; Unfolded Protein Response ; Valosin Containing Protein/antagonists & inhibitors
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2022-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-22-0167
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Article ; Online: Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

Bioorganic & medicinal chemistry letters

2021 Volume 41, Page(s) 127974

Abstract: Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in ... ...

Abstract	Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
MeSH term(s)	Aniline Compounds/chemistry ; Aniline Compounds/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Design ; Ethers/chemistry ; Ethers/pharmacology ; Humans ; L-Lactate Dehydrogenase/antagonists & inhibitors ; L-Lactate Dehydrogenase/chemistry ; L-Lactate Dehydrogenase/metabolism
Chemical Substances	Aniline Compounds ; Antineoplastic Agents ; Ethers ; L-Lactate Dehydrogenase (EC 1.1.1.27)
Language	English
Publishing date	2021-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2021.127974
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Article ; Online: Discovery and Optimization of 2

Rohde, Jason M / Karavadhi, Surendra / Pragani, Rajan / Liu, Li / Fang, Yuhong / Zhang, Weihe / McIver, Andrew / Zheng, Hongchao / Liu, Qingyang / Davis, Mindy I / Urban, Daniel J / Lee, Tobie D / Cheff, Dorian M / Hollingshead, Melinda / Henderson, Mark J / Martinez, Natalia J / Brimacombe, Kyle R / Yasgar, Adam / Zhao, Wei /

Klumpp-Thomas, Carleen / Michael, Sam / Covey, Joseph / Moore, William J / Stott, Gordon M / Li, Zhuyin / Simeonov, Anton / Jadhav, Ajit / Frye, Stephen / Hall, Matthew D / Shen, Min / Wang, Xiaodong / Patnaik, Samarjit / Boxer, Matthew B

Journal of medicinal chemistry

2021 Volume 64, Issue 8, Page(s) 4913–4946

Abstract: Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro- ... ...

Abstract	Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2
MeSH term(s)	Animals ; Brain/metabolism ; Cell Line, Tumor ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/therapeutic use ; Female ; Glycine/analogs & derivatives ; Glycine/therapeutic use ; Half-Life ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Mice ; Mice, Nude ; Microsomes, Liver/metabolism ; Mutagenesis, Site-Directed ; Neoplasms/drug therapy ; Neoplasms/pathology ; Pyridines/therapeutic use ; Pyridones/chemistry ; Pyridones/metabolism ; Pyridones/therapeutic use ; Rats ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays
Chemical Substances	Enzyme Inhibitors ; Pyridines ; Pyridones ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; IDH1 protein, human (EC 1.1.1.42.) ; ivosidenib (Q2PCN8MAM6) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c00019
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