Hydrogen-bond surrogate peptides and peptidomimetics for p53 reactivation
The present invention relates to peptidomimetics for reactivating p53. Methods of using the peptidomimetics are also disclosed.
1. A peptidomimetic, wherein the peptidomimetic is selected from the group consisting of:
(i) a compound of Formula Ia, Ib, Ic, Id, Ie, or If:
wherein:
B is C(R 1 )(R 1′ ), O, S, or NR 1 ;
is a double bond and each R 1′ is absent; or is a single bond and each R 1′ is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
each R 1 is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; and
wherein:
(a) at least one R 1 at the positions labeled “Glu” is a glutamic acid side chain,
(b) at least one R 1 at the positions labeled “Leu” is a leucine side chain,
(c) at least one R 1 at the positions labeled “Ala” is an alanine side chain,
(d) at least one R 1 at the positions labeled “Arg” is an arginine side chain,
(e) at least one R 1 at the positions labeled “Asp” is an aspartic acid side chain, and
(f) at least one R 1 at the positions labeled “Gln” is a glutamine side chain;
R 2 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:
R 2′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
R 3 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B:
R 3′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
each R 4 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
R 4′ is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ ,R 4 ) and B;
a is one or two;
each b is independently one or two;
c is one or two;
each d is independently one or two;
m′ is zero or any number;
m″ is zero or any number;
n′ and n″ are each independently zero, one, two, three, or four;
each o is independently one or two; and
p is one or two;
(ii) a compound of Formula IIa, IIb, IIc, IId, or, IIe:
wherein:
each R 1 is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; and
wherein:
(a) at least one R 1 at the positions labeled “Glu” is a glutamic acid side chain,
(b) at least one R 1 at the positions labeled “Leu” is a leucine side chain,
(c) at least one R 1 at the positions labeled “Ala” is an alanine side chain,
(d) at least one R 1 at the positions labeled “Arg” is an arginine side chain,
(e) at least one R 1 at the positions labeled “Asp” is an aspartic acid side chain, and
(f) at least one R 1 at the positions labeled “Gln” is a glutamine side chain;
R 2 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:
R 2′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
R 3 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B:
R 3′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
each b is independently one or two;
c is one or two;
each d is independently one or two;
m′ is zero or any number;
m″ is zero or any number;
each o is independently one or two;
one of p′ and p″ is zero and the other is zero or one;
one of q′ and q″ is zero and the other is zero or one;
s is one, two, three, four, or five; and
Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond; and
(iii) a compound of Formula IIIa:
wherein:
B is C(R 1 )(R 1′ ), O, S, or NR 1 ;
is a double bond and each R 1′ is absent; or is a single bond and each R 1′ is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
each R 1 is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; and
wherein:
(a) at least one R 1 at the positions labeled “Glu” is a glutamic acid side chain,
(b) at least one R 1 at the positions labeled “Leu” is a leucine side chain,
(c) at least one R 1 at the positions labeled “Ala” is an alanine side chain,
(d) at least one R 1 at the positions labeled “Arg” is an arginine side chain,
(e) at least one R 1 at the positions labeled “Asp” is an aspartic acid side chain, and
(f) at least one R 1 at the positions labeled “Gln” is a glutamine side chain;
R 2 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:
wherein:
R 2′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
m′ is zero or any number;
each b is independently one or two; and
c is one or two;
R 3 is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B:
wherein:
R 3′ is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5 wherein R 5 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2 wherein each R 5 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;
m″ is zero or any number; and
each d is independently one or two;
each R 4 is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;
R 4′ is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ ,R 4 ) and B;
n′ and n″ are each independently zero, one, two, three, or four;
each o is independently one or two;
p is one or two;
one of p′ and p″ is zero and the other is zero or one;
one of q′ and q″ is zero and the other is zero or one;
s is one, two, three, four, or five; and
Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond.
2. The peptidomimetic according to claim 1 , wherein B is C(R 1 )(R 1′ ).
3. The peptidomimetic according to claim 1 , wherein B is O.
4. The peptidomimetic according to claim 1 , wherein B is S.
5. The peptidomimetic according to claim 1 , wherein B is NR 1 .
6. The peptidomimetic according to claim 1 , wherein 9 to 12 atoms form the backbone of the macrocycle portion of the compound.
7. The peptidomimetic according to claim 1 , wherein 12 to 15 atoms form the backbone of the macrocycle portion of the compound.
8. The peptidomimetic according to claim 1 , wherein 15 to 18 atoms form the backbone of the macrocycle portion of the compound.
9. The peptidomimetic according to claim 1 , wherein 20 to 24 atoms form the backbone of the macrocycle portion of the compound.
10. The peptidomimetic according to claim 1 , wherein the peptidomimetic is a compound of Formula IIa, and R 2 is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl.
11. A pharmaceutical composition comprising a peptidomimetic according to claim 1 and a pharmaceutically acceptable vehicle.
12. The pharmaceutical composition according to claim 11 , wherein the peptidomimetic is a compound of Formula Ia, IIa, or IIIa.