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Therapeutic methods relating to hsp90 inhbitors

一种抑制剂、治疗剂的技术，应用在HSP90抑制剂领域，能够解决没有HSP90抑制剂测试、未获准用于人类等问题

Pending Publication Date: 2020-07-03
AI THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, none of these compounds has been approved for use in humans, and no HSP90 inhibitor has been tested in genetically defined populations

Method used

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  • Therapeutic methods relating to hsp90 inhbitors
  • Therapeutic methods relating to hsp90 inhbitors
  • Therapeutic methods relating to hsp90 inhbitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0235] Example 1: MPC-0767 Inhibits Cell Viability of NSCLC Cell Lines Carrying EGFR and HER2 Mutations

[0236] NSCLC cell lines HCC-827 (EGFR L858R), H1975 (EGFR L858R / T790M) PC-9 (EGFR DelE746_A750) and H1781 (HER2 G7776insV G / C) were treated with MPC-0767 at concentrations ranging from 98 - 50000 nM3 days, use CellTiter-Glo after this time ® Reagents to determine cell viability. Figure 1 shows HCC-827 ( Figure 1A ), H1975 ( Figure 1B ), PC-9 ( Figure 1C ) and H1781 ( Figure 1D ) dose-response curve of the cell line. All ECs 50 The values ​​are all within the clinically achievable concentration range.

[0237] To verify the mechanism of cell viability loss, H1975 cells were treated with MPC-0767 (0.7 µM) for 72 hours. After this time, cells were stained with 7-aminoactinomycin D (7-AAD) and annexin V (markers of cell membrane integrity and apoptosis), respectively. like figure 2 As shown, treatment of H1975 cells with MPC-0767 (0.7 µM) resulted in a decrease i...

Embodiment 2

[0242] Example 2: MPC-0767 exhibits potent anti-leukemic activity in AML cells with FLT3-ITD

[0243] Exponentially growing cell lines were counted and seeded into 96-well clear flat-bottom polystyrene microtiter plates at a final volume of 90 µL per well. For primary AML samples, cells were split in 2 x 10 4 Cells were seeded into 384-well plates in a final volume of 27 µL per well. For treatment of cell lines or primary samples, 10 µL or 3 µL of 10X concentration of MPC-0767 is then added to the cells to make final concentrations of 10000 nM, 5000 nM, 2500 nM, 1250 nM, 625 nM, 313 nM, respectively , 156 nM, 78 nM, 39 and 20 nM. For comparison, cells were treated with the FLT3 inhibitor gitertinib (100 nM, 50 nM, 25 nM, 12.5 nM, 6.3 nM, 3.1 nM, 1.6 nM, 0.8 nM, 0.4 and 0.2 nM). Cells were seeded and processed in duplicate. After 3 days of incubation, cell viability was determined by adding 100 µL per well of a 96-well plate or 30 µL per well of a 384-well plate by measurin...

Embodiment 3

[0246] Example 3: MPC-0767 is cytotoxic in primary AML cells with FLT3-ITD

[0247] To test whether the anti-leukemic effect of MPC-0767 was due to induction of cell death, 4 primary AML samples (all with FLT3-ITD) were treated with increasing concentrations of MPC-0767 for 72 hours. Samples were then processed to quantify cells positive for Annexin V and 7AAD by flow cytometry. These markers allow detection of cell death, specifically, death (positive for 7-AAD only), early apoptosis (positive for Annexin V only), or late apoptosis / necrosis (positive for 7-ADD and Annexin V) ) population combination to give a cell death readout.

[0248] Such as Figure 6 As shown, primary AML samples treated with MPC-0767 showed a dose-dependent increase in cell death. Notably, one of the samples (Y1265) was obtained from a patient who relapsed on gitertinib.

[0249] These findings suggest that MPC-0767 induces cell death in primary AML samples with FLT3-ITD by inducing apoptosis. In a...

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Abstract

The disclosure provides methods for treating cancer, including but not limited to, hematopoietic and lung cancers, using the HSP90 inhibitor, MPC-0767, as monotherapy and in combination therapy with additional active agents, including but not limited to, inhibitors of Bcl-2, EZH2 inhibitors, Ras / Raf / MEK / ERK pathway inhibitors, checkpoint inhibitors, DNMT inhibitors, ATO and chemotherapeutic agents. The disclosure also provides related compositions and methods of use.

Description

[0001] field of invention [0002] The present invention relates to the use of HSP90 inhibitors for treating cancer. [0003] Background of the invention [0004] Heat shock proteins (HSPs) are a class of chaperone proteins that are involved in various cellular processes such as temperature rise, external stress and nutrient deprivation. Its essential role as a chaperone is to stabilize the protein under such stress, but also to promote the correct folding of client proteins. [0005] HSP90 is a highly conserved, widely expressed molecular chaperone that plays an important role in regulating the post-translational folding, stability and function of cellular proteins (often referred to as "client proteins"), especially in response to stress (Whitesell and Lindquist, Nature Rev. Cancer 2005 5:761). The folding of client proteins depends on the ATPase activity of HSP90, and HSP90 inhibitors that bind to the ATP site can lead to degradation of client proteins through the ubiquiti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/52A61P35/00A61K45/06A61K31/435A61K31/4709A61K31/496A61K31/704A61K31/7068
CPCA61K45/06A61K31/435A61K31/496A61K31/704A61K31/7068A61K31/52A61K31/553A61P35/00A61K31/506A61K31/4725A61K31/337A61K31/5377A61K31/4709A61K31/095A61K31/357A61K31/4184A61K2300/00A61K9/0019A61K31/517A61K31/444A61K31/4412A61K31/519A61P35/02C12Q1/6886C12Q2600/156C12Q2600/106
Inventor H.利钦斯坦N.比哈里S.兰德雷特S.盖尔J.格罗茨克M.赫尔南德斯P.R.杨J.M.罗思伯格
Owner AI THERAPEUTICS INC
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