Activity of IPI-504, a Novel Heat-Shock Protein 90 Inhibitor, in Patients With Molecularly Defined Non–Small-Cell Lung Cancer

Sequist, Lecia V.; Gettinger, Scott; Senzer, Neil; Martins, Renato; Jänne, Pasi A.; Lilenbaum, Rogerio; Gray, Jhanelle E.; Iafrate, A. John; Katayama, Ryohei; Hafeez, Nafeeza; Sweeney, Jennifer; Walker, John R.; Fritz, Christian; Ross, Robert W.; Grayzel, David; Engelman, Jeffrey A.; Borger, Darrell R.; Paez, G.; Natale, Ronald B.

doi:10.1200/jco.2010.30.8338

Cited by 309 publications

(216 citation statements)

References 26 publications

Supporting

Mentioning

212

Contrasting

Order By: Relevance

“…To date, there are 13 new Hsp90 inhibitors at various stages of clinical development (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The earlier geldanamycin analogues (i.e., 17-AAG or 17-DMAG), despite potent in vitro and in vivo preclinical activity, have not shown clear clinical benefit (5,31).…”

Section: Discussionmentioning

confidence: 99%

“…NVP-HSP990 is highly potent and selective for Hsp90 and represents one of the most potent oral Hsp90 inhibitors reported (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The GTL-16 model was selected as a screening model due to its growth and survival dependency on the Hsp90 client protein c-Met (24).…”

Section: Discussionmentioning

confidence: 99%

“…All other Hsp90 inhibitors are fully synthetic small molecules that fall into distinct structural classes including: (i) resorcinol-containing molecules (NVP-AUY922, KW-2478, STA-9090, and AT13387), (ii) purine scaffold (BIIB021, PU-H71, and MPC-3100), (iii) imidazopyridine (Debio 0932), (iv) 2-aminoterephthalamide (XL888), and (v) aminopyrimidine (NVP-HSP990). The chemical structures of BIIB028 and DS- 2248 have not yet been disclosed (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, 13 synthetic Hsp90 inhibitors are under assessment in oncology clinical trials. Six inhibitors (IPI-504, NVP-AUY922, KW-2478, STA-9090, AT13387, and BIIB-028) are administered intravenously, whereas 7 (BIIB-021, IPI-493, XL-888, MPC-3100, DS-2248, Debio 0932, and NVP-HSP990) are dosed orally (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). These inhibitors address some key pharmaceutical limitations of 17-AAG (5-7).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC 50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC 50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…TAS-116 addresses the issues that have hampered the clinical development of HSP90 inhibitors because it shows a favorable tissue distribution profile. One of the most notable HSP90-related adverse events universally observed but to differing degrees in the clinic is visual disturbance (18)(19)(20)(21)(45)(46)(47)(48). The observed symptoms include night blindness, photopsia, blurred vision, and visual impairment, which are likely associated with retinal dysfunction (20,21).…”

Section: Discussionmentioning

confidence: 99%

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Ohkubo

Kodama

Muraoka

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo [3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90a and b that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90a and b alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.

show abstract

Mechanisms of Resistance to Epidermal Growth Factor Receptor (EGFR) in Non‐Small Cell Lung Cancer

Massarelli

2014

Lung Cancer

View full text Add to dashboard Cite

Activity of IPI-504, a Novel Heat-Shock Protein 90 Inhibitor, in Patients With Molecularly Defined Non–Small-Cell Lung Cancer

Abstract: IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

Cited by 309 publications

References 26 publications

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Mechanisms of Resistance to Epidermal Growth Factor Receptor (EGFR) in Non‐Small Cell Lung Cancer

Contact Info

Product

Resources

About