Heterocyclic mitochondrial activity inhibitors and uses thereof
A heteroaryl and cycloalkyl technology, applied in the field of inhibiting mitochondrial activity, can solve problems such as unsustainable and incomplete reactions
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Embodiment 1
[0729] Example 1: Materials and methods
[0730] human leukemia sample
[0731] This study was approved by the Research Ethics Board (REB) of the University of Montreal, Maisonneuve-Rosemont Hospital and Charles Lemoyne Hospital (Longueuil, QC, Canada). All AML samples were collected with informed consent between 2001 and 2017, according to the procedures of the Quebec Council for Cell Research (BCLQ). Cord blood (CB) units were collected from consenting mothers and used Positive selection kit to isolate human CD34 + CB cells (StemCell Technologies, Vancouver, Canada, catalog number 18056) (Fares et al., Science. 2014 Sep 19;345(6203):1509-12).
[0732] chemical screening
[0733] Primary cells: Frozen AML monocytes were thawed at 37°C in Iscove's Modified Dulbecco's Medium (IMDM) containing 20% FBS and DNase I (100 μg / mL). Cells were then cultured in optimized AML growth medium as previously reported (Pabst, C. et al., Nature methods 11, 436-442, 2014): IMDM, 15% ...
Embodiment 2
[0754] Example 2: Patients with HOX-high AML generally have a poor prognosis.
[0755] showed consistent high expression of genes belonging to the HOX network in cell samples ( Figure 1A ) was associated with a significant reduction in overall survival of patients ( Figure 1B ). Figure 1C showed a correlation between HOXA9 and HOXA10 expression in leukemia cells, and Figure 1D showed that the survival of AML patients belonging to the HOXA9 / HOXA10 high group was similar to Figure 1B Survival of patients belonging to the HOX-network high subgroup is shown in , suggesting that high expression of HOXA9 and HOXA10 can be used as a surrogate for detecting HOX network-high patients. Taken together, these data show that patients with AML cells exhibiting high expression of HOX-network genes have a poor prognosis and will benefit from appropriate AML treatment.
Embodiment 3
[0756] Example 3: Moritinib effectively inhibits HOX-high AML cells
[0757] Assess the following: HOX-high versus HOX-medium / low in exposure to 60 targeted receptor tyrosine kinase (RTK) inhibitors using high-expressing HOXA9 and HOXA10 as a surrogate for detection of HOX-network-high patient samples Specimen survival, RAS and members of the PI3K pathway ( Figure 2A ).
[0758] HOX-high patient cells were significantly more sensitive to the RTK ERBB2 inhibitor moritinib when compared to HOX-medium / low samples ( Figure 2B ). No statistically significant differences in sensitivity were observed for the other compounds tested.
[0759] A dose-response validation screen of a large cohort of AML samples confirmed that HOX-high patient cells were significantly more sensitive to moritinib compared to HOX-intermediate / low AML cells ( Figure 2C -D). Moritinib EC in the tested AML population 50 The median is about 375nM ( Figure 2E ). Patients belonging to the moritinib sen...
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