Geldanamycin derivative and method of treating cancer same

Abstract

A geldanamycin derivative exhibiting significant preliminary in vivo activity, particularly significant oral in vivo activity, and a method of treating or preventing cancer in a host comprising administrering a geldanamycin derivative to a host in an amount sufficient to treat or prevent cancer.

Description

[0001] Cross References to Related Applications

[0002] This patent application claims priority to US Provisional Patent Application 60 / 280,078, filed March 30,2001. technical field

[0003] The present invention relates to geldanamycin, more specifically to new geldanamycin derivatives, pharmaceutical compositions thereof, and methods for preventing and treating cancer using these derivatives. Background technique

[0004] The ErbB2 gene product, which is a member of the ErbB family of tyrosine kinase receptors, is believed to play an important role in malignant tumor cells. Studies have shown that overexpression of ErbB2 causes cellular transformation and tumorigenesis, and in vitro experiments have shown that ErbB2 is required to induce tumor cell invasion by other members of the ErbB family. The benzoquinones ansamycin and geldanamycin have antitumor activity in vivo and have been shown to cause rapid depletion of ErbB2 protein levels. Geldanamycin is a specific inhib...

Examples

Embodiment 1

[0066] This example shows the in vivo activity of compounds of the invention compared to geldanamycin derivatives of similar structure.

[0067] Compounds A-C were subjected to hollow fiber assays as described above. Compounds A and B were mixed with saline and Tween 80 (0.05%) to give two dose levels of 75 mg / kg / dose and 50 mg / kg / dose, respectively. Compound C was also mixed with saline and Tween 80 (0.05%) to give two dose levels of 20 mg / kg / dose and 13.4 mg / kg / dose, respectively. Optimal dosage levels were determined from previous toxicology studies, therefore, the dosage used represents the upper limit that can be administered to the host without inducing toxic effects. All three compounds were administered by intraperitoneal injection once daily for four days. After 4 days, the hollow fibers were removed from the mice and the MTT assay described above was performed. The HFA score for each compound was determined from the calculation of percent cell growth inhibition [(...

Embodiment 2

[0071] This example shows the oral in vivo activity of the compounds of the invention.

[0072]As described above, hollow fiber detection was performed using compound B of the present invention. Compound B was mixed with water to give two dosage levels of 75 mg / kg / dose and 50 mg / kg / dose, respectively. Compound B was then administered orally (PO) once a day for four days. After 4 days, the hollow fibers were removed from the mice and the MTT assay described above was performed. The HFA score for each compound was determined from the calculation of percent cell growth inhibition [(1-(% treated net growth / % control net growth))*100], as shown in Table 2.

[0073] compound

[0074] According to the above results, Compound B of the present invention exhibited significant in vivo anticancer activity in oral administration.

[0001] Cross References to Related Applications

[0002] This patent application claims priority to US Provisional Patent Application 60 / 280,078, filed March 30,2001. technical field

[0003] The present invention relates to geldanamycin, more specifically to new geldanamycin derivatives, pharmaceutical compositions thereof, and methods for preventing and treating cancer using these derivatives. Background technique

[0004] The ErbB2 gene product, which is a member of the ErbB family of tyrosine kinase receptors, is believed to play an important role in malignant tumor cells. Studies have shown that overexpression of ErbB2 causes cellular transformation and tumorigenesis, and in vitro experiments have shown that ErbB2 is required to induce tumor cell invasion by other members of the ErbB family. The benzoquinones ansamycin and geldanamycin have antitumor activity in vivo and have been shown to cause rapid depletion of ErbB2 protein levels. Geldanamycin is a specific inhib...

Examples

Embodiment 1

[0066] This example shows the in vivo activity of compounds of the invention compared to geldanamycin derivatives of similar structure.

[0067] Compounds A-C were subjected to hollow fiber assays as described above. Compounds A and B were mixed with saline and Tween 80 (0.05%) to give two dose levels of 75 mg / kg / dose and 50 mg / kg / dose, respectively. Compound C was also mixed with saline and Tween 80 (0.05%) to give two dose levels of 20 mg / kg / dose and 13.4 mg / kg / dose, respectively. Optimal dosage levels were determined from previous toxicology studies, therefore, the dosage used represents the upper limit that can be administered to the host without inducing toxic effects. All three compounds were administered by intraperitoneal injection once daily for four days. After 4 days, the hollow fibers were removed from the mice and the MTT assay described above was performed. The HFA score for each compound was determined from the calculation of percent cell growth inhibition [(...

Embodiment 2

[0071] This example shows the oral in vivo activity of the compounds of the invention.

[0072]As described above, hollow fiber detection was performed using compound B of the present invention. Compound B was mixed with water to give two dosage levels of 75 mg / kg / dose and 50 mg / kg / dose, respectively. Compound B was then administered orally (PO) once a day for four days. After 4 days, the hollow fibers were removed from the mice and the MTT assay described above was performed. The HFA score for each compound was determined from the calculation of percent cell growth inhibition [(1-(% treated net growth / % control net growth))*100], as shown in Table 2.

[0073] compound

[0074] According to the above results, Compound B of the present invention exhibited significant in vivo anticancer activity in oral administration.

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