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Methods of treating cancer with HDAC inhibitors

An inhibitor and dosage technology, applied in the direction of anhydride/acid/halide active ingredients, etc., can solve the problem of not disclosing favorable pharmacokinetic characteristics, etc.

Inactive Publication Date: 2006-11-29
MERCK HDAC RESEARCH LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Importantly, the aforementioned patents do not disclose oral formulations with favorable pharmacokinetic characteristics, such as high bioavailability, which results in high blood levels of the active compound over prolonged periods of time

Method used

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  • Methods of treating cancer with HDAC inhibitors
  • Methods of treating cancer with HDAC inhibitors
  • Methods of treating cancer with HDAC inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0402] Synthetic SAHA

[0403] SAHA may be synthesized as outlined below, or by the method described in US Patent No. 5,369,108, the contents of which are incorporated herein by reference in its entirety, or by any other method.

[0404] Synthetic SAHA

[0405] Step 1 - Synthesis of Suberanilic acid

[0406]

[0407] In a 22 L flask, 3,500 g (20.09 mol) of suberic acid was added, and the acid was heated to melt. The temperature was raised to 175° C., and then 2,040 g (21.92 mol) of aniline were added. The temperature was raised to 190° C. and maintained at this temperature for 20 minutes. The melt was poured into a Nalgene tank containing 4,017 g of potassium hydroxide in 50 L of water. The mixture was stirred for 20 minutes, then the melt was added. The reaction was repeated on the same scale and a second batch of the melt was poured into the same potassium hydroxide solution. After the mixture was stirred well, the stirrer was turned off and th...

Embodiment 2

[0420] Oral suberoylanilide hydroxamic acid (SAHA)

[0421] Background: Treatment with hybrid polar cell differentiating agents results in growth inhibition of cell lines and xenografts derived from human solid tumors. This effect is mediated in part by inhibition of histone deacetylases. SAHA has been found in laboratory and preclinical studies to be a potent histone deacetylase inhibitor with the ability to induce tumor cell growth arrest, differentiation and apoptosis.

[0422] Objective: To define a safe daily oral regimen of SAHA that can be used in a phase II study. In addition, the pharmacokinetic profile of the SAHA oral formulation was evaluated. The bioavailability and antineoplastic therapeutic effects of oral SAHA in humans were also monitored under fasted and non-fasted conditions. In addition, the biological effects of SAHA on normal tissues and tumor cells were evaluated, and the responses to histone acetylation levels were recorded.

[0423]Patients: Patien...

Embodiment 3

[0431] Oral suberoylanilide hydroxamic acid (SAHA) - dose escalation

[0432] In another experiment, as shown in Table 4, 25 patients with solid tumors were enrolled in group A, 13 patients with Hodgkin's or non-Hodgkin's lymphoma were enrolled in group B, and one patient with acute leukemia and one patient with myelodysplastic syndrome were enrolled in group C.

[0433] Group

dosage

(mg / day)

Dosing regimen

Days of administration

Withdrawal period

Program Patient#

(Group A / Group B / Group C) *

I

200

once a day

continuous

none

6 / 0 / 0

II

400

once a day

continuous

none

5 / 4 / 2

III

400

q12 hours

continuous

none

6 / 3 / 0

IV

600

once a day

continuous

none

4 / 3 / 0

V

200

q12 hours

continuous

none

4 / 3 / 0

VI

300

q12 hours

continuous

none

- / - / -

...

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Abstract

The present invention relates to methods of treating cancers, e.g., mesothelioma or lymphoma. More specifically, the present invention relates to methods of treating mesothelioma or diffuse large B-cell lymphoma (DLBCL), by administration of pharmaceutical compositions comprising HDAC inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly give rise to high blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.

Description

[0001] Statement of Government Interests [0002] This invention was made in whole or in part with government support provided by the National Cancer Institute under grant number 1R21CA 096228-01. The government may have certain rights in this invention. field of invention [0003] The present invention relates to methods of treating cancer such as mesothelioma or lymphoma. More specifically, the present invention relates to the treatment of mesothelioma, diffuse large B-cell lymphoma (DLBCL) by administering a pharmaceutical composition comprising an HDAC inhibitor such as suberoylanilide hydroxamic acid (SAHA). ) or other cancer or tumor methods. Oral formulations of these pharmaceutical compositions have favorable pharmacokinetic characteristics such as high bioavailability and unexpectedly result in high blood levels of the active compound over prolonged periods of time. Background of the invention [000...

Claims

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Application Information

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IPC IPC(8): A61K31/185
Inventor N·G·巴科波洛斯J·H·奇奥T·A·米勒C·M·帕拉迪塞V·M·里奇翁
Owner MERCK HDAC RESEARCH LLC
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