Transient protection of hematopoietic stem and progenitor cells against ionizing radiation

Patent metadata

Field	Value
Publication number	US-2019167691-A1
Application number	US-201916268317-A
Country	US
Kind code	A1
Filing date	Feb 5, 2019
Priority date	Mar 15, 2013
Publication date	Jun 6, 2019
Grant date	—

Abstract

This invention is in the area of improved compounds and methods for transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC), from the damage associated with ionizing radiation (IR) exposure using selective radioprotectants.

First claim

1 . A method of reducing ionizing radiation induced apoptosis in hematopoietic stem cells and/or progenitor cells (HSPCs) in a human exposed to ionizing radiation, the method comprising administering to the human an effective amount of a CDK4/6 inhibitor compound having the structure:

or its pharmaceutically acceptable salt, wherein the CDK4/6 inhibitor compound is administered up to about 24 hours after exposure to the ionizing radiation.

2 . The method of claim 1 , wherein the CDK4/6 inhibitor compound is administered up to about 12 hours after exposure to the ionizing radiation.

3 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a human receiving ionizing radiation for the treatment of a CDK4/6 replication independent cellular proliferation disorder, the method comprising administering to the human an effective amount of a CDK4/6 inhibitor compound having the structure:

or its pharmaceutically acceptable salt;
wherein the CDK4/6 inhibitor is administered less than about 4 hours prior to receiving ionizing radiation.

4 . The method of claim 3 , wherein the cellular proliferation disorder is a CDK4/6 replication independent cancer.

5 . The method of claim 3 , wherein administration of the CDK4/6 inhibitor compound does not affect growth of diseased cells.

6 . The method of claim 3 , wherein the human is further treated with hematopoietic growth factors upon dissipation of the CDK4/6 inhibitor's inhibitory effect.

7 . The method of claim 6 , wherein the hematopoietic growth factor is selected form the group consisting of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin (EPO).

8 . A method of reducing ionizing radiation induced apoptosis in cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a human exposed to ionizing radiation, the method comprising administering to the human an effective amount of a CDK4/6 inhibitor compound having the structure:

or its pharmaceutically acceptable salt, wherein the CDK4/6 inhibitor compound is administered up to about 24 hours after exposure to the ionizing radiation.

9 . The method of claim 8 , wherein the CDK4/6 inhibitor compound is administered up to about 12 hours after exposure to the ionizing radiation.

10 . A method for reducing the effect of ionizing radiation exposure on cyclin-dependent kinase 4 (CDK4) replication-dependent hematopoietic stem cells and/or progenitor cells (HSPCs) in a human receiving ionizing radiation for the treatment of a CDK4/6 replication independent cellular proliferation disorder, the method comprising administering to the human an effective amount of a CDK4/6 inhibitor compound having the structure:

or its pharmaceutically acceptable salt;
wherein the CDK4/6 inhibitor is administered less than about 4 hours prior to receiving ionizing radiation.

11 . The method of claim 10 , wherein the cellular proliferation disorder is a CDK4/6 replication independent cancer.

12 . The method of claim 10 , wherein administration of the CDK4/6 inhibitor compound does not affect growth of diseased cells.

13 . The method of claim 10 , wherein the human is further treated with hematopoietic growth factors upon dissipation of the CDK4/6 inhibitor's inhibitory effect.

14 . The method of claim 13 , wherein the hematopoietic growth factor is selected form the group consisting of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin (EPO).

Assignees

• G1 Therapeutics Inc

Inventors

• Strum Jay Copeland
• Bisi John Emerson
• Roberts Patrick Joseph
• Tavares Francis Xavier

Classifications

• A61K38/208

  IL-12 · CPC title

• A61K31/527 Primary

  spiro-condensed · CPC title

• A61K38/196

  Thrombopoietin · CPC title

• A61K38/18

  Growth factors; Growth regulators · CPC title

• A61N2005/1094

  Shielding, protecting against radiation · CPC title