COMPOUNDS FOR TREATING ABNORMAL CELLULAR PROLIFERATION
Provided herein are compounds, compositions and methods for treating disorders mediated by abnormal cellular proliferation and processes for identifying such compounds.
1 - 93 . (canceled)
94 . A process for identifying a therapeutic agent that selectively inhibits the growth of, or induces apoptosis in, in a cancer stem cell by:
a. identifying at least one candidate compound;
b. contacting a plurality of normal conditionally immortalized hematopoietic stem cells with the candidate compound;
c. contacting a plurality of leukemic cancer stem cells with the candidate compound;
d. detecting or measuring the impact of the candidate compound on the viability of the plurality of normal conditionally immortalized hematopoietic stem cells and the plurality of leukemic cancer stem cells; and
e. comparing the impact of the candidate compound on viability of the plurality of normal conditionally immortalized hematopoietic stem cells to the impact of the candidate compound on viability of the plurality of leukemic cancer stem cells.
95 . The process of claim 94 , wherein the plurality of normal conditionally immortalized hematopoietic stem cells is generated by a method comprising contacting a population of hematopoietic stem cells with recombinant MYC-ER and BCL-2 polypeptides.
96 . The process of claim 94 , wherein the plurality of normal conditionally immortalized hematopoietic stem cells is generated by a method comprising contacting a population of hematopoietic stem cells with: a recombinant MYC-ER polypeptide, wherein the MYC-ER polypeptide is selected from Tat-MYC-ER or Vpr-MYC ER; and a recombinant BCL-2 polypeptide, wherein the BCL-2 polypeptide is Tat-Bcl-2 or Vpr-Bcl-2.
97 . The process of claim 94 , wherein the plurality of leukemic cancer stem cell is generated by a method comprising:
a. contacting a population of hematopoietic stem cells with (1) recombinant MYC-ER polypeptide, wherein the MYC-ER polypeptide is selected from Tat-MYC-ER or Vpr-MYC ER; and (ii) recombinant BCL-2 polypeptide, wherein the BCL-2 polypeptide is Tat-Bcl-2 or Vpr-Bcl-2; and
b. limiting dilution of the population of hematopoietic stem cells without any helper or feeder cells.
98 . The process of claim 94 , wherein detecting or measuring the impact of the candidate compound on viability of the normal conditionally immortalized hematopoietic stem cell and the leukemic cancer stem cell is achieved by 7AAD staining, a GFP viability assay, or a combination thereof.
99 . A therapeutic agent identified by the process of claim 94 .
100 . A method of selectively inducing apoptosis in or inhibiting the growth of a cancer stem cell relative to a normal hematopoietic stem cell, comprising contacting the cell with an effective amount of a compound identified by the process of claim 94 .
101 . The method of claim 100 , wherein the cancer stem-cell is a hematological cancer stem cell.
102 . The method of claim 100 , wherein the cancer stem cell is a leukemic stem cell.
103 . The method of claim 100 , wherein the cancer stem cell is present in an individual diagnosed with, is suspected of having, or is predisposed to develop cancer.