Inhibition of proline catabolism for the treatment of cancer and other therapeutic applications

Patent metadata

Field	Value
Publication number	US-10517844-B2
Application number	US-201515519504-A
Country	US
Kind code	B2
Filing date	Nov 12, 2015
Priority date	Nov 13, 2014
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

In various embodiments a cancer treatment method is provided based on inhibition of proline catabolism. When combined with p53 restoration therapy and/or inhibition of glutaminase, the inhibition of proline catabolism results in a “synthetic lethal” and synergistic anticancer response. Novel suicide inhibitors that induce the degradation of proline dehydrogenase (PRODH) are also provided. Also provided is a method of assaying PRODH to identify responders/non-responders to inhibition of proline catabolism and/or glutaminase.

First claim

What is claimed is:

1. An analog of N-propargylglycine (PPG) that is capable of occupying the proline binding pocket of proline dehydrogenase (PRODH) and forming a covalent bond with PRODH or a flavin adenine dinucleotide (FAD) cofactor of PRODH, wherein the PPG analog comprises a compound with the formula:

wherein R 1 is selected from the group consisting of H, C 1 -C 4 alkyl, halogen, and C 1 -C 4 haloalkyl.

2. The PPG analog of claim 1 , wherein R 1 is selected from the group consisting of H, methyl, ethyl, isopropyl, isobutyl, Br, Cl, F, CF 3 , and CCl 3 .

3. The PPG analog of claim 1 , wherein R 1 is H.

4. The PPG analog of claim 1 , wherein R 1 is methyl.

5. The PPG analog of claim 1 , wherein the PPG analog is a substantially pure S-enantiomer.

6. A pharmaceutical formulation comprising:
a PPG analog of claim 1 ; and
a drug that promotes p53 restoration; and/or
a drug that inhibits glutaminase (GLS).

7. The pharmaceutical formulation of claim 6 , wherein R 1 is selected from the group consisting of H, methyl, ethyl, isopropyl, isobutyl, Br, Cl, F, CF 3 , and CCl 3 .

8. The pharmaceutical formulation of claim 7 , wherein R 1 is H.

9. The pharmaceutical formulation of claim 7 , wherein R 1 is methyl.

10. The pharmaceutical formulation of claim 6 , wherein said PPG analog is a substantially pure S-enantiomer or a substantially pure R-enantiomer.

11. A pharmaceutical formulation comprising:
a PPG analog of claim 1 ; and
a pharmaceutically acceptable carrier.

12. The pharmaceutical formulation of claim 11 , wherein R 1 is H.

13. The pharmaceutical formulation of claim 12 , wherein R 1 is methyl.

14. The pharmaceutical formulation of claim 11 , wherein said formulation is a unit dosage formulation.

15. The pharmaceutical formulation of claim 11 , wherein said formulation is formulated for administration via a route selected from the group consisting of oral administration, transdermal administration, parenteral administration, aerosol administration, administration via inhalation, intravenous or intra-arterial administration, local administration via injection or cannula, and rectal administration.

16. The pharmaceutical formulation of claim 11 , wherein said formulation is formulated for oral administration.

17. The pharmaceutical formulation of claim 11 , wherein said formulation is formulated for administration into or near a solid tumor.

18. The pharmaceutical formulation claim 11 , wherein said formulation is formulated for oral administration.

19. The PPG analog of claim 1 , wherein the PPG analog is a substantially pure R-enantiomer.

Assignees

• Buck Inst Res Aging

Inventors

• Scott Gary K
• Benz Christopher C

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• G01N33/57515

  of the breast · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C07C229/20

  the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups · CPC title