Method and compositions for predicting anti-cancer efficacy of compounds targeting apoptosis pathway

Patent metadata

Field	Value
Publication number	US-12287338-B2
Application number	US-202017297188-A
Country	US
Kind code	B2
Filing date	Nov 27, 2020
Priority date	Nov 27, 2019
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

Abstract

Provided are biomarkers for predicting the efficacy of MDM2 inhibitor or Bcl-2/Bcl-xL dual inhibitors or Bcl-2 inhibitor or Bcl-xL inhibitor in treating cancer patients. Also provided are compositions, e.g., kits, for evaluating gene levels of the biomarkers and methods of using such gene levels to predict a cancer patient's response to the MDM2 inhibitors or Bcl-2/Bcl-xL dual inhibitors or Bcl-2 inhibitor or Bcl-xL inhibitor. Such information can be used in determining prognosis and treatment options for cancer patients.

First claim

What is claimed is:

1. A method for treating a cancer in a subject in need thereof, the method comprising:
a) measuring a level of at least one biomarker comprising Noxa and ASCL1 in a test sample derived from the subject;
b) comparing the level of the at least one biomarker comprising Noxa and ASCL1 with a corresponding reference level of the at least one biomarker comprising Noxa and ASCL1 to determine difference from the reference level; and
c) administering to the subject an amount of an MDM2 inhibitor, a Bcl-2/Bcl-xL dual inhibitor, a Bcl-xL inhibitor, or a Bcl-2 inhibitor to the subject-if the difference exceeds a predetermined threshold,
wherein:
i) the MDM2 inhibitor is

or a pharmaceutically acceptable salt thereof,
ii) the Bcl-2/Bcl-xL dual inhibitor is
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carbonyloxy)ethylphosphonic acid, having the following structure:

or a pharmaceutically acceptable salt thereof; or
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carboxylic acid, having the following structure:

or a pharmaceutically acceptable salt thereof, and
iii) the Bcl-2/Bcl-xL dual inhibitor, Bcl-xL inhibitor, or Bcl-2 inhibitor is selected from the compounds having the following structures:

2. A method for identifying a subject having a cancer as likely to respond to treatment with an MDM2 inhibitor, a Bcl-2/Bcl-xL dual inhibitor, a Bcl-xL inhibitor, or a Bcl-2 inhibitor, the method comprising:
a) measuring a level of at least one biomarker comprising Noxa and ASCL1 in a test sample derived from the subject;
b) comparing the level of the at least one biomarker comprising Noxa and ASCL1 with a corresponding reference level of the at least one biomarker comprising Noxa and ASCL1 to determine difference from the reference level; and
c) identifying the subject as likely to respond to the treatment with the MDM2 inhibitor, the Bcl-2/Bcl-xL dual inhibitor, the Bcl-xL inhibitor, or the Bcl-2 inhibitor if the difference exceeds a predetermined threshold,
wherein:
i) the MDM2 inhibitor is

or a pharmaceutically acceptable salt thereof,
ii) the Bcl-2/Bcl-xL dual inhibitor is
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carbonyloxy)ethylphosphonic acid, having the following structure

or a pharmaceutically acceptable salt thereof; or
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carboxylic acid, having the following structure:

or a pharmaceutically acceptable salt thereof, and
iii) the Bcl-2/Bcl-xL dual inhibitor, Bcl-xL inhibitor, or Bcl-2 inhibitor is selected from the compounds having the following structures:

3. A method for monitoring therapeutic efficacy in a subject having a cancer and having been treated with an MDM2 inhibitor, a Bcl-2/Bcl-xL dual inhibitor, a Bcl-xL inhibitor, or a Bcl-2 inhibitor for a therapeutic period, the method comprising:
a) obtaining a test sample from the subject after the therapeutic period;
b) measuring a level of at least one biomarker comprising Noxa and ASCL1 in the test sample to obtain a post-treatment level of the at least one biomarker comprising Noxa and ASCL1;
c) comparing the post-treatment level with a baseline level of the at least one biomarker comprising Noxa and ASCL1 in the test sample derived from the subject before the therapeutic period, to determine post-treatment change in the level of the at least one biomarker comprising Noxa and ASCL1; and
d1) when the post-treatment change exceeds a predetermined threshold, then continuing administering to the subject the MDM2 inhibitor, the Bcl-2/Bcl-xL dual inhibitor, the Bcl-xL inhibitor, or the Bcl-2 inhibitor to the subject, or
d2) when the post-treatment change does not reach the predetermined threshold, then (d2-1) increasing the dose of the MDM2 inhibitor, the Bcl-2/Bcl-xL dual inhibitor, the Bcl-xL inhibitor, or the Bcl-2 inhibitor to the subject, (d2-2) administering to the subject an amount of a second anti-cancer therapeutic agent in combination with the MDM2 inhibitor, the Bcl-2/Bcl-xL dual inhibitor, the Bcl-xL inhibitor, or the Bcl-2 inhibitor, or (d2-3) discontinuing administering to the subject the MDM2 inhibitor, the Bcl-2/Bcl-xL dual inhibitor, the Bcl-xL inhibitor, or the Bcl-2 inhibitor,
wherein;
(i) the MDM2 inhibitor is

or a pharmaceutically acceptable salt thereof,
(ii) the Bcl-2/Bcl-xL dual inhibitor is
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carbonyloxy)ethylphosphonic acid, having the following structure;

or a pharmaceutically acceptable salt thereof; or
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H-pyrrol-3-yl)-5-fluorophenyl) piperazin-1-yl)phenyl) sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl) piperidine-4-carboxylic acid, having the following structure:

or a pharmaceutically acceptable salt thereof, and
(iii) the Bcl-2/Bcl-xL dual inhibitor, Bcl-xL inhibitor, or Bcl-2 inhibitor is selected from the compounds having the following structures:

4. The method of claim 1 , wherein the cancer is a solid tumor or a hematological cancer, wherein
the solid tumor is selected from adrenocortical carcinoma, anal cancer, astrocytoma, childhood cerebellar or cerebral, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumor, brain cancer, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroect

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Zhai Yifan
• Yang Dajun
• Fang Douglas Dong
• Tao Ran

Classifications

• G01N33/5758 Primary

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• G01N33/57595

  involving intracellular compounds · CPC title

• G01N33/57585

  involving compounds identifiable in body fluids · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title