Combination therapy for treating cancer

A cancer and compound technology, applied in drug combinations, antibody medical components, chemical instruments and methods, etc., can solve problems such as drug resistance in patients

Pending Publication Date: 2022-05-27
GUANGZHOU SHUNJIAN PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the first generation BCR-ABL TKI imatinib and several second-generation TKIs offer clinical benefit, but many patients still develop resistance
This acquired resistance to TKIs is a major challenge in CML treatment

Method used

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  • Combination therapy for treating cancer
  • Combination therapy for treating cancer
  • Combination therapy for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0066] Embodiment 1 A method of treating cancer comprising co-administering to a subject in need thereof:

[0067] a) a compound of formula (I) or a pharmaceutically acceptable salt thereof; and

[0068] b) allosteric inhibitors;

[0069] wherein formula (I) has the following structure:

[0070]

[0071] in

[0072] R 1 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 alkoxy or phenyl; and

[0073] R 2 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogen.

[0074] In one embodiment of the compound of formula (I), R 1 is hydrogen or C 1-4 alkyl.

[0075] In another embodiment of the compounds of formula (I), R 1 is hydrogen.

[0076] In another embodiment of the compounds of formula (I), R 2 is hydrogen or C 1-4 alkyl.

[0077] In another embodiment of the compounds of formula (I), R 2 is C 1-4 alkyl.

[0078] In another embodiment of the compounds of formula (I), R 2 is methyl or ethyl. In another embodiment, R 2 is methyl.

[0079] In another emb...

Embodiment approach 2

[0082] Embodiment 2 The method of Embodiment 1, wherein the compound of formula (I) is HQP-1351 or a pharmaceutically acceptable salt thereof, wherein HQP-1351 has the following structure:

[0083]

[0084]HQP-1351 is a novel, orally active, potent third-generation BCR-ABL inhibitor designed to efficiently target BCR-ABL mutants, including T315I, and it is being developed for the treatment of first and third-generation BCR-ABL Second-generation tyrosine kinase inhibitors (TKIs).

[0085] The chemical name for HQP-1351 is 3-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methyl ylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-benzamide.

[0086] The compound of formula (I) or the HQP-1351 compound or a pharmaceutically acceptable salt thereof can be prepared according to the production methods described in US Pat. No. 8,846,671B2, issued September 30, 2014, which is incorporated herein by reference, its entirety and for all purposes or methods similar ther...

Embodiment approach 3

[0087] Embodiment 3 The method of Embodiment 1 or 2 wherein the allosteric inhibitor is asciminib.

[0088] The present inventors found that HQP-1351, also known as orebatinib, enhanced the effect of allosteric inhibitors on the resistance conferred by the BCR-ABL compound mutation. Treatment with a tyrosine kinase inhibitor (TKI) targeting the BCR-ABL ATP binding site promotes recovery from Ph+ leukemia. However, the emergence of the checkpoint mutation T315I and compound mutants confers resistance to these TKIs. HQP-1351 is a new generation TKI targeting BCR-ABL. It is an ATP site inhibitor currently in development for r / rCML.

[0089] Asciminib is an allosteric inhibitor that targets the myristoyl binding pocket and downstream signaling of the BCR-ABL kinase. Studies have shown that combining asciminib with ponatinib can only overcome some of the resistance caused by the BCR-ABL compound mutant. The novel combination of HQP-1351 and asciminib, targeting the ATP pocket a...

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Abstract

The present invention relates to one or more combination treatments of cancer patients using a compound of formula (I) as described herein and an allosteric inhibitor or an immune checkpoint molecule.

Description

technical field [0001] The present invention relates to one or more combination therapy of cancer patients using a compound of formula (I) as described herein and an allosteric inhibitor or immune checkpoint molecule. Background technique [0002] Chronic myeloid leukemia (CML) is a rare hematological malignancy with an annual incidence of approximately 1.9 cases / 100,000. BCR-ABL tyrosine kinase inhibitors (TKIs) have significantly improved the clinical management of CML. However, despite the first-generation BCR-ABL TKI imatinib and several second-generation TKIs offer clinical benefit, but many patients still develop resistance. This acquired resistance to TKIs is a major challenge in CML therapy. BCR-ABL kinase mutations are a key mechanism of acquired resistance, and T315I is the most common resistance mutation, occurring in approximately 25% of patients with drug-resistant CML. Patients with T315I mutation are resistant to both first- and second-generation BCR-ABL ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/496A61K31/4439A61K39/395A61P35/00A61P35/02
CPCA61K31/496A61K31/4439A61K39/3955A61K45/06A61P35/00A61P35/02A61K2300/00A61K31/437C07D471/04A61K31/497C07D401/14A61K2039/505C07K16/2827A61K39/39558
Inventor 翟一帆杨大俊王光凤邱妙珍罗繁
Owner GUANGZHOU SHUNJIAN PHARM CO LTD
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