Universitéde Montreal

British Columbia Cancer Agency Branch

Rsem, Limited Partnership

Fred Hutchinson Cancer Center

Valorisation-recherche, Limited Partnership

Adaerata, Limited Partnership

Institut De Recherche Cliniques De Montréal

Fred Hutchinson Cancer Research Center

Guy Sauvageau

Stéphane Gingras

Yves Gareau

Iman Fares

Anne Marinier

Jalila Chagraoui

Gaoqiang Yang

Yves Chantigny

Keith Richard Humphries

Irène Baccelli

Bruno Simoneau

Rejean Ruel

Hans-Peter Kiem

Yves Andre Chantigny

Denis-Claude Roy

Réjean Ruel

Jean-Sébastien Delisle

Nathalie Beslu

Nicole Martin

Sylvain Meloche

Josee Hebert

Marc Saba El-Leil

Caroline Pabst

Jonathan Yeh

Sandra Cohen

Jean Roy

Silvy Lachance

Heterocyclic compounds of Formula I: and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (NK), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.

Heterocyclic mitochondrial activity inhibitors and uses thereof

It is provided a method of expanding dendritic (DC) cells and/or natural killer (NK) cells in vivo in a patient comprising the steps of producing a graft of stem and progenitor cells cultured with UM171 or analogues therefrom and expanded before being administered to the patient. The expansion or increase in dendritic (DC) cells and/or natural killer (NK) cells population in the patient results in an increase immune response reducing transplant related mortality (TRM), severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections.

Expansion of NK and DC cells in vivo mediating immune response

Heterocyclic compounds of Formula (I) and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (A/K), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.

It is provided a method of expanding ex vivo hematopoietic stem cells (HSC), the method comprising selecting a population of Endothelial Protein C Receptor (EPCR)HSC, culturing the selected HSC thereby expanding said EPCRHSC and the use of the expanded EPCRHSC for stem cells transplantation.

Selection of human hematopoetic stem cells using EPCR

The invention relates to compounds as described herein and pharmaceutical compositions containing them. Also, the invention relates to methods for expanding stem cells and/or progenitor cells and methods for treating a hematopoietic disorder/malignancy, an autoimmune disease and/or an inherited immunodeficient disease.

Compounds and use thereof in the expansion of stem cells and/or progenitor cells

Compounds of general formula or salts or prodrugs thereof, are provided and described herein. The compounds are useful to expand hematopoietic stem cell and/or hematopoietic progenitor cell populations. Particularly, the hematopoietic cells are human cells. The compounds are also useful in the medical treatment of hematopoietic disorder/malignancy, an autoimmune disease and/or an inherited immune-deficient disease in a subject. 

Compounds and use thereof in the expansion of hematopoietic stem cells and/or hematopoietic progenitor cells

Pyrimido[4,5-b]indole derivatives are provided. These compounds are useful to expand hematopoietic stem cell populations, particularly, human hematopoietic stem cell populations. The compounds are also useful in the medical treatment of diseases that involve hematopoietic stem cells.

Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells

Methods and compositions for enhancing viral gene transfer, such as lentiviral gene transfer, and improving the efficacy of gene delivery to cells such as primitive hematopoietic cells, are described. These methods and compositions are based on the use of pyrimido[4,5-b]indole derivatives. Cell-based compositions and methods useful for therapeutic indications amenable to treatment with gene therapies, including hematopoietic stem cell therapies, are also described.

Compounds and methods for enhancing viral gene transfer to human hematopoietic cells

Novel methods for modulating acute myeloid leukemia stem/progenitor cell expansion and/or differentiation are disclosed. These methods are based on the use of aryl hydrocarbon receptor (AhR) modulators and/or compounds of formula I or II  Screening assays to identify compounds that may be useful for inhibiting and/or eliminating AML initiating cells using AhR modulators and/or the compounds of formula I or II are also disclosed. The use of pharmaceutically acceptable agonists of the AhR for preventing or inhibiting minimal residual disease (MRD) in an AML patient is also disclosed.

Methods to modulate acute myeloid leukemia stem/progenitor cell expansion and/or differentiation

A polypeptide, the amino acid sequence of which comprises a sequence as set forth in SEQ ID NO:2, including at least one mutation within the degron domain of the polypeptide encompassed between positions 1 and 35 of the sequence, wherein said at least one mutation reduces the susceptibility of the polypeptide to ubiquitin-proteasome degradation.

Mutated HOXB4 proteins with improved stability, and methods of use thereof

The present invention relates to a method for determining a predisposition to develop cancer in a patient, comprising the step of detecting EN 2 gene or its expression product in said patient or in a biological sample of said patient, whereby detecting presence of at least one of EN 2 gene or its expression product is indicative of a predisposition to develop breast cancer. The present invention also relates to antisense hybridizine to EN2 gene kits for determining predisposition to develop cancer and method of reducing EN2 expression.

Methods for determining a predisposition to develop breast adenocarcinoma or breast inflammatory carcinoma

Growing community of inventors

Montréal, Canada

Guy Sauvageau