"目錄號: HY-14463

Cell Cycle/DNA DamageMetabolic Enzyme/Protease-

AT13387是Hsp90抑制劑，對A375細(xì)胞的IC50為18 nM吴旋，具有長效的抗腫瘤活性逸吵。

HSP

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生物活性

Description

AT13387 is a selective potent Hsp90 inhibitor with IC50 of 18 nM in A375 cells, displays a long duration of anti-tumor activity.IC50 Value: 18 nM Target: Hsp90in vitro: AT13387 is a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins. AT13387 is a selective potent heat shock protein 90 (Hsp90) inhibitor with IC50 of 18 nM in A375 cells. The Kd for AT13387 binding is 0.7 nM.in vivo: AT13387 could be tolerated at doses of up to 70 mg/kg twice weekly or 90 mg/kg once weekly. Body weight loss in mice does not exceed 20% before recovering in all cases except one, and loss is highest following the second dose. Tumor growth inhibition is similar in NCI-H1975 for both dosing regimens. The maintenance of antitumor effects with such a prolonged off-treatment period is consistent with the extended pharmacodynamic action of AT13387 observed for mutant EGFR and other biomarkers in vitro and in vivo and the extended retention of AT13387 in tumors.

Clinical Trial

NCT01294202

Astex Pharmaceuticals

Gastrointestinal Stromal Tumor (GIST)

March 2011

Phase 2

NCT01712217

Astex Pharmaceuticals

Non-small Cell Lung Cancer(NSCLC)

October 2012

Phase 1-Phase 2

NCT01246102

National Cancer Institute (NCI)-National Institutes of Health Clinical Center (CC)

Solid Tumors-Breast Cancer

November 1, 2010

Phase 1

NCT01685268

Astex Pharmaceuticals

Prostate Cancer

September 2012

Phase 1-Phase 2

NCT02627430

National Cancer Institute (NCI)

Adult Solid Neoplasm-Estrogen Receptor Negative-Fallopian Tube Serous Neoplasm-HER2/Neu Negative-Ovarian Serous Adenocarcinoma-Ovarian Serous Tumor-Primary Peritoneal Serous Adenocarcinoma-Progesterone Receptor Negative-Recurrent Breast Carcinoma-Recurrent Fallopian Tube Carcinoma-Recurrent Ovarian Carcinoma-Recurrent Primary Peritoneal Carcinoma-Triple-Negative Breast Carcinoma

March 2016

Phase 1

NCT00878423

Astex Pharmaceuticals

Metastatic Solid Tumors

May 2008

Phase 1

NCT01294202

Astex Pharmaceuticals

Gastrointestinal Stromal Tumor (GIST)

March 2011

Phase 2

NCT01712217

Astex Pharmaceuticals

Non-small Cell Lung Cancer(NSCLC)

October 2012

Phase 1-Phase 2

NCT01246102

National Cancer Institute (NCI)-National Institutes of Health Clinical Center (CC)

Solid Tumors-Breast Cancer

November 1, 2010

Phase 1

NCT01685268

Astex Pharmaceuticals

Prostate Cancer

September 2012

Phase 1-Phase 2

NCT02627430

National Cancer Institute (NCI)

Adult Solid Neoplasm-Estrogen Receptor Negative-Fallopian Tube Serous Neoplasm-HER2/Neu Negative-Ovarian Serous Adenocarcinoma-Ovarian Serous Tumor-Primary Peritoneal Serous Adenocarcinoma-Progesterone Receptor Negative-Recurrent Breast Carcinoma-Recurrent Fallopian Tube Carcinoma-Recurrent Ovarian Carcinoma-Recurrent Primary Peritoneal Carcinoma-Triple-Negative Breast Carcinoma

March 2016

Phase 1

NCT00878423

Astex Pharmaceuticals

Metastatic Solid Tumors

May 2008

Phase 1

NCT02503709

National Cancer Institute (NCI)

Advanced Malignant Solid Neoplasm-Metastatic Malignant Solid Neoplasm-Unresectable Solid Neoplasm

April 8, 2016

Phase 1

NCT02572453

National Cancer Institute (NCI)

ALK Positive-BCL6 Positive-Recurrent Anaplastic Large Cell Lymphoma-Recurrent Diffuse Large B-Cell Lymphoma-Recurrent Mantle Cell Lymphoma-Refractory Anaplastic Large Cell Lymphoma-Refractory Diffuse Large B-Cell Lymphoma-Refractory Mantle Cell Lymphoma

April 4, 2016

Phase 2

NCT02535338

National Cancer Institute (NCI)

EGFR Activating Mutation-EGFR Exon 20 Insertion Mutation-Recurrent Non-Small Cell Lung Carcinoma-Stage IV Non-Small Cell Lung Cancer AJCC v7

January 21, 2016

Phase 1-Phase 2

NCT02474173

National Cancer Institute (NCI)

Estrogen Receptor Negative-HER2/Neu Negative-Progesterone Receptor Negative-Recurrent Breast Carcinoma-Stage III Breast Cancer-Stage IIIA Breast Cancer-Stage IIIB Breast Cancer-Stage IIIC Breast Cancer-Stage IV Breast Cancer-Triple-Negative Breast Carcinoma

January 15, 2016

Phase 1

NCT02097225

National Cancer Institute (NCI)

BRAF V600E Mutation Present-BRAF V600K Mutation Present-Metastatic Malignant Solid Neoplasm-Recurrent Malignant Solid Neoplasm-Recurrent Melanoma-Stage III Skin Melanoma-Stage IIIA Skin Melanoma-Stage IIIB Skin Melanoma-Stage IIIC Skin Melanoma-Stage IV Skin Melanoma-Unresectable Solid Neoplasm

May 29, 2014

Phase 1

NCT02898207

National Cancer Institute (NCI)

Estrogen Receptor Negative-HER2/Neu Negative-High Grade Fallopian Tube Serous Adenocarcinoma-High Grade Ovarian Serous Adenocarcinoma-Metastatic Malignant Solid Neoplasm-Primary Peritoneal High Grade Serous Adenocarcinoma-Progesterone Receptor Negative-Recurrent Breast Carcinoma-Recurrent Fallopian Tube Carcinoma-Recurrent Ovarian Carcinoma-Recurrent Primary Peritoneal Carcinoma-Triple-Negative Breast Carcinoma-Unresectable Solid Neoplasm

May 19, 2017

Phase 1

NCT02381535

National Cancer Institute (NCI)

Human Papillomavirus Infection-Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7-Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7-Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7-Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7-Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7-Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7-Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7-Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7-Stage IVB

September 21, 2015

Phase 1

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References

[1].Woodhead AJ, Angove H, Carr MG et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69.

[2].Graham B, Curry J, Smyth T et al. The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci. 2012 Mar;103(3):522-7.

[3].Smyth T, Van Looy T, Curry JE et al. The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and -resistant gastrointestinal stromal tumor models. Mol Cancer Ther. 2012 Aug;11(8):1799-808.

[4].Kang MH, Reynolds CP, Houghton PJ et al. Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jul 15;59(1):185-8.

[5].Study to Assess the Safety of Escalating Doses of AT13387 in Patients With Metastatic Solid Tumors

[6].Active Clinical Trials with AT13387