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Compounds and compositions for treating hematological disorders

A compound, leukemia technology, applied in drug combinations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of AML death and low survival rate

Pending Publication Date: 2020-01-14
奥锐金肿瘤有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, AML often relapses after complete remission, and for many patients, relapsed AML leads to death
Specifically, in the setting of relapse, the very low survival rate has been a serious concern

Method used

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  • Compounds and compositions for treating hematological disorders
  • Compounds and compositions for treating hematological disorders
  • Compounds and compositions for treating hematological disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0339] Example 1: Inhibition of FLT-3 by Compound A

[0340] Compounds were tested for inhibition of FLT-3 wild type using the substrate peptide EAIYAAPFAKKK. Flt3(h) (14-500, GenBank NM_004119) was incubated with 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 50 μM EAYAAPFAKKK, 10 mM magnesium acetate and [γ-33P]-ATP (specific activity and concentration as required) education. The reaction was initiated by addition of Mg / ATP mixture. After 40 minutes of incubation at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. 10 [mu]L of the reaction was then spotted onto a P30 filter pad, washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[0341] Compound A was tested against Flt-3 using the Eurofins standard KinaseProfiler assay as described above. Compound A was also tested against IRAK1 and Flt-3(D835Y) using the same protocol as the substrates myelin basic protein (MBP) and ...

Embodiment 2

[0352] Example 2: In vitro assay of AML model MV4-11

[0353] The CellTiter Glo Luminescent Cell Viability Assay is a highly sensitive homogeneous assay for the determination of the number of viable cells in culture based on the quantification of ATP levels in metabolically active cells. Addition of CTG reagent results in cell lysis and a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present. Luminescence was measured using a multilabel reader capable of measuring luminescence. An increase or decrease in cell number causes a corresponding change in luminescence levels, indicating the effect of the test material on cell proliferation.

[0354] Preparation of solutions / reagents

[0355] Preparation of CTG reagent:

[0356] Thaw CellTiter-Glo Buffer and equilibrate to room temperature. The lyophilized CellTiter-Glo substrate was brought to room temperature. CTG reagent was prepared by mixing...

Embodiment 3

[0377] Example 3: Inhibition of Cell Proliferation in the MV4-11 Xenograft Model

[0378] Using the procedure of Example 2, Compounds A and B were evaluated to determine % inhibition of proliferation in MV4-11 cells. IC of Compound A 50 0.031μM ( Figure 2A ), IC of Compound B 50 6.1e-005μM ( Figure 2B ).

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PUM

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Abstract

The present invention provides methods for treating hematological disorders, such as acute myeloid leukemia, by the use of substituted heterocyclic compounds and pharmaceutically acceptable salts thereof. The compounds inhibit IRAK4 and FLT-3 kinases.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority from Indian Provisional Patent Application Serial No. 201741011785 filed on March 31, 2017, which is hereby incorporated by reference in its entirety. Background technique [0003] Acute myeloid leukemia (hereinafter also referred to as "AML") is a hematological malignancy with a poor prognosis, usually occurring in adults, and its 5-year survival rate is estimated to be 20%. Currently, AML therapy temporarily reduces the number of AML cells to levels below the limit of detection. This condition is called a "complete remission." However, AML often relapses after complete remission, and for many patients, relapsed AML leads to death. In particular, in the case of relapse, the extremely low survival rate has been a serious concern. Therefore, new treatments for AML are needed. Contents of the invention [0004] Provided herein is a method of treating or preventing acute...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00
CPCA61K31/416A61K31/422A61K31/437A61K31/4439A61K31/444A61K31/5355A61K45/06A61P35/02A61K31/4545A61K31/5377
Inventor V.R.冈马迪S.萨马达K.内洛尔G.达吉纳卡特W.R.巴拉苏布拉马尼安
Owner 奥锐金肿瘤有限公司
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