- Patent Number:
9,421,203
- Appl. No:
14/564186
- Application Filed:
December 09, 2014
- نبذة مختصرة :
The invention provides methods for overriding cell cycle arrest in a tumor cell, which comprise inducing DNA damage in the cell, and contacting the cell with an amount of bosutinib or a bosutinib isomer effective to inhibit one or more kinase constituents of a DNA damage checkpoint pathway. The invention also provides novel bosutinib isomers, as well as compositions of the novel isomers and the bosutinib isomer 3,5-dichloro-4-methoxyaniline.
- Inventors:
Institute for Cancer Research (Philadelphia, PA, US)
- Assignees:
Institute for Cancer Research (Philadelphia, PA, US)
- Claim:
1. A method for treating a tumor in a subject in need thereof, comprising inducing DNA damage in a cell of the tumor, and administering to the subject an effective amount of a bosutinib isomer of Formula II: [chemical expression included] (II), or a pharmaceutically acceptable salt thereof, thereby treating the tumor.
- Claim:
2. The method of claim 1 , wherein inducing DNA damage in the cell comprises irradiating the cell in the subject.
- Claim:
3. The method of claim 1 , wherein inducing DNA damage in the cell comprises administering to the subject an effective amount of an agent that damages DNA.
- Claim:
4. The method of claim 3 , wherein the agent comprises an alkylating agent.
- Claim:
5. The method of claim 3 , wherein the agent comprises a pyrimidine analog.
- Claim:
6. The method of claim 3 , wherein the agent comprises gemcitabine.
- Claim:
7. The method of claim 1 , wherein the tumor is a tumor of the pancreas, lung, head and neck, kidney, hematopoietic system, breast, ovary, colon, lymph nodes, bladder, prostate gland, stomach, or esophagus.
- Claim:
8. The method of claim 6 , wherein the bosutinib isomer of Formula II reduces the LC 50 of gemcitabine to less than about 10 nM.
- Claim:
9. The method of claim 6 , wherein the bosutinib isomer of Formula II reduces the LC 50 of gemcitabine to less than about 5 nM.
- Claim:
10. The method of claim 6 , wherein the bosutinib isomer of Formula II reduces the LC 50 of gemcitabine to about 3 nM or less.
- Claim:
11. A method for treating a tumor in a subject in need thereof, comprising inducing DNA damage in a cell of the tumor, and administering to the subject an effective amount of a bosutinib isomer of Formula IV: [chemical expression included] (IV), or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 3 is independently selected from the group consisting of F, Br, and I, and wherein R 2 is selected from the group consisting of H and N, thereby treating the tumor.
- Claim:
12. The method of claim 11 , wherein inducing DNA damage in the cell comprises irradiating the cell in the subject.
- Claim:
13. The method of claim 11 , wherein inducing DNA damage in the cell comprises administering to the subject an effective amount of an agent that damages DNA.
- Claim:
14. The method of claim 13 , wherein the agent comprises an alkylating agent.
- Claim:
15. The method of claim 13 , wherein the agent comprises a pyrimidine analog.
- Claim:
16. The method of claim 13 , wherein the agent comprises gemcitabine.
- Claim:
17. The method of claim 11 , wherein the tumor is a tumor of the pancreas, lung, head and neck, kidney, hematopoietic system, breast, ovary, colon, lymph nodes, bladder, prostate gland, stomach, or esophagus.
- Claim:
18. The method of claim 1 , wherein the tumor is a tumor of the pancreas.
- Claim:
19. The method of claim 6 , wherein the tumor is a tumor of the pancreas.
- Claim:
20. The method of claim 11 , wherein the tumor is a tumor of the pancreas.
- Claim:
21. The method of claim 16 , wherein the tumor is a tumor of the pancreas.
- Patent References Cited:
6002008 December 1999 Wissner et al.
7070968 July 2006 Kufe
7417148 August 2008 Boschelli et al.
7767678 August 2010 Tesconi et al.
7919625 April 2011 Boschelli et al.
RE42376 May 2011 Wissner et al.
2003/0082685 May 2003 Weischselbaum et al.
2007/0010527 January 2007 Boschelli
2008/0033175 February 2008 Sutherland et al.
2010/0028346 February 2010 Lutz et al.
2010/0216828 August 2010 Dierks et al.
2013/0210024 August 2013 Yu
- Other References:
Boschelli et al., caplus an 2006:211292. cited by examiner
Golas-et-al-2, caplus an 2005:513607. cited by examiner
Goias et al., caplus 2003:72680. cited by examiner
Bosutinib, 2016, http://www.selleckchem.com/products/Bosutinib.html. cited by examiner
RN 1428126-92-4, 2013. cited by examiner
Rajeshkumar, et al., “MK-1775, a Potent Wee1 Inhibitor, Synergizes with Gemcitabine to Achieve Tumor Regressions, Selectively in p53—Deficient Pancreatic Cancer Zenografts”, Clin. Cancer Res., 17(9) May 1, 2011, 2799-2806. cited by applicant
Levinson, et al., “Structural and Spectroscopic Anaylsis of the Kinase Inhibitor Bosutinib and an Isomer of Bosutinib Binding to the Abl Tyrosine Kinase Domain”, PLoS ONE, 7(4): e29828, doi:10.1371/journal.pone.0029828, 2015. cited by applicant
Golas, et al., “SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models”, Cancer Res., 65(12), Jun. 15, 2005, pp. 5358-5364. cited by applicant
International Search Report and Written Opinion issued in related International Application PCT/US2013/031344 dated May 23, 2013. cited by applicant
- Primary Examiner:
Yoo, Sun Jae
- Attorney, Agent or Firm:
Stradley Ronon Stevens & Young, LLP
- الرقم المعرف:
edspgr.09421203
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