STING crystals and modulators

Patent metadata

Field	Value
Publication number	US-10176292-B2
Application number	US-201414908019-A
Country	US
Kind code	B2
Filing date	Jul 31, 2014
Priority date	Jul 31, 2013
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The present invention provides STING crystals. The present invention also provides STING modulators that interact with sites present in and/or defined by such crystals. The present invention also provides methods of making and using such crystals and modulators. Other aspects and/or features of the present invention will be apparent to those skilled in the art, reading the present specification.

First claim

We claim:

1. A method of designing a stimulator of interferon genes (STING) modulator, comprising:
providing the structural coordinates on a computer of a human STING H232 C-terminal domain in a closed conformation according to Table 1;
identifying a binding pocket comprising a potential interaction site, wherein the potential interaction site contains amino acid residues corresponding to Ser162, Tyr167, Arg238, Tyr240, and Glu260 of the human STING H232 C-terminal domain, as set forth in SEQ ID NO. 1; and
determining whether a moiety docks with the binding pocket and forms binding interactions with Ser162, Tyr167, Arg238, Tyr240, and Glu260, wherein a moiety that docks with the binding pocket and forms binding interactions with Ser162, Tyr167, Arg238, Tyr240, and Glu260 is a STING modulator structural element, wherein the binding interaction with Arg238 comprises a stacking interaction.

2. The method of claim 1 , wherein whether a moiety docks with the binding pocket is determined by assessing one or more features selected from the group consisting of: spatial separation between the moiety and Ser162, Tyr167, Arg238, Tyr240, and Glu260; energy of interaction between the moiety and Ser162, Tyr167, Arg238, Tyr240, and Glu260, and combinations thereof.

3. The method of claim 1 , wherein the step of determining whether a moiety docks with the binding pocket comprises a step of providing a new image of the moiety docked with the binding pocket.

4. The method of claim 3 , further comprising a step of comparing the new image with a structure of a human STING H232 C-terminal domain bound to a known modulator.

5. The method of claim 1 , wherein the structural coordinates are obtained from a crystallographic structure determination of the human STING H232 C-terminal domain crystallized as a homodimer having c[G(2′,5′)pA(3′,5′)p] bound in a binding pocket formed at the interface between the two human STING H232 C-terminal domains in the homodimer.

6. The method of claim 1 , wherein one of the binding interactions is a water-mediated hydrogen bond.

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Rockefeller
• Univ Rutgers
• Univ Of Bonn

Inventors

• Patel Dinshaw J
• Tuschl Thomas
• Jones Roger
• Hartmann Gunther
• Barchet Winfried
• Zillinger Thomas
• Wang Weiyi
• Gao Pu
• Deng Liang
• Ascano Jr Manuel

Classifications

• G01N2333/52

  Assays involving cytokines · CPC title

• A61K31/473

  ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines · CPC title

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title