Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for tor kinase inhibitory activity

• US 9,557,338 B2
• Filed: 08/26/2015
• Issued: 01/31/2017
• Est. Priority Date: 10/18/2012
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Xu, Weiming, Mortensen, Deborah, Xu, Shuichan, Fultz, Kimberly Elizabeth
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US14/835,817
• Publication Number:
  US 20150362505A1
• Time in Patent Office: 524 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/485 involving kinase
• CPC Class Codes: G01N 2333/9121 with an alcohol group as acceptor (2.7.1), e.g. general tyrosine, serine or threonine kinases
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/7028 Cancer
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/6842 Proteomic analysis of subsets of protein mixtures with reduced complexity, e.g. membrane proteins, phosphoproteins, organelle proteins

Abstract

Provided herein are methods for treating a cancer treatable by inhibition of phosphorylation of PRAS40, GSK3β or p70S6K1, comprising administering an effective amount of a TOR kinase inhibitor to a patient having a cancer treatable by inhibition of phosphorylation of PRAS40, GSK3β or p70S6K1.

Claims

1. A method for detecting or measuring the inhibition of TOR kinase activity in a patient having cancer, comprising measuring the amount of phosphorylated PRAS40, GSK3β

or p70S6K1 in a biological sample from said patient, prior to and after the administration of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient.

2. A method for determining whether a patient having cancer is sensitive to 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, comprising administering said patient said 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and determining whether or not TOR kinase activity is inhibited in said patient by measuring the amount of phosphorylated PRAS40, GSK3β

or p70S6K1 in a biological sample from said patient, prior to and after the administration of said 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient.

3. A method for determining the effective amount of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof for the treatment of a cancer treatable by inhibition of phosphorylation of PRAS40, GSK3β

and/or p70S6K1 in a patient having cancer, comprising administering said patient varying doses of said 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and determining the amount of TOR kinase activity inhibition in said patient resulting from each dose of said 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof by measuring the amount of phosphorylated PRAS40, GSK3β

or p70S6K1 in a biological sample from said patient, prior to and after the administration of each dose of said 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient.

4. The method of claim 3, the cancer is prostate cancer, lung cancer, colon cancer, glioma or breast cancer.