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US 11,142,554 B2Granted
Selective Mcl-1 binding peptides
AssigneesMassachusetts Institute of Technology, Dana-Farber Cancer Institute, Inc.
InventorsRaheleh Rezaei-Araghi, Amy Keating, Gregory H. Bird, Loren Walensky
Life of this patent
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Abstract
Provided herein are stabilized peptides that bind Mcl-1. Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that include administering to a subject one of the polypeptides.
Claims16
A compound comprising an internally cross-linked polypeptide comprising the amino acid sequence:
- (SEQ ID NO:
- 1)
- F1 G1 A2 B2 C2 D2 E2 F2 G2 A3 B3 C3 D3 E3 F3 G3 A4
- B4 C4 D4 E4 F4 G4 A5,
- wherein:
- F1 is R or is missing;
- G1 is P or is missing;
- A2 is E or is missing;
- B2 is I;
- C2 is W;
- D2 is M, L, F, I, or norleuicine (Nle);
- E2 is T, A, V, or Aib;
- F2 is Q, or R;
- G2 is G, H, E, or S;
- A3 is L, or I;
- B3 is R, D, Q, Aib, or Me-Leu;
- C3 is R;
- D3 is L, or I;
- E3 is G;
- F3 is D;
- G3 is E;
- A4 is I, V, or F;
- B4 is N;
- C4 is A;
- D4 is Y or R;
- E4 is Y;
- F4 is A or is missing;
- G4 is R or is missing;
- A5 is R or is missing;
- and
- the side chains of two amino acids separated by two, three or six amino acids are replaced by an internal cross-link;
- the side chains of three amino acids are replaced by an internal stitch;
- the side chains of four amino acids are replaced by internal cross-links or internal stitches,;
- or the side chains of at least four amino acids are replaced by internal cross-links, internal stitches, or a combination of internal cross-links and stitches,
- wherein the cross-link is between the alpha carbons of:
- E2 and B3;
- F2 and C3;
- or B4 and F4.
35 more elements
A compound comprising a polypeptide having a sequence selected from the group consisting of:
- (SEQ ID NO:
- 2)
- RPEIWMTQGLRRLGDEINAYYAR,
- (M1;
- SEQ ID NO:
- 6)
- IWNleTQGLRRLGDEINAYYARR,
- and
- (B1;
- SEQ ID NO:
- 23)
- IWFAQEIDRIGDEVNAYYARR;
- wherein:
- none or one, of the amino acids are replaced by another amino acid, and the side chains of two amino acids are replaced by an internal crosslink,
- wherein the cross-link is between the alpha carbons of:
- E2 and B3;
- F2 and C3;
- or B4 and F4.
15 more elements
Dependencies are inferred from the claim text.