p53 modulators and uses thereof
View Patent ↗Described herein, inter alia, are p53 modulator compounds and methods of using the same. In an aspect is provided a p53 protein covalently bonded to a compound described herein. In an aspect is provided a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient. In an aspect is provided a method of treating cancer in a subject in need of such treatment, including administering to the subject an effective amount of a compound described herein.
1 . A compound having the formula:
wherein
L 1 is a bond or covalent linker;
R 1 is a transcriptional coactivator binding moiety, wherein the transcriptional coactivator binding moiety is a BRD4 binding moiety, wherein the BRD4 binding moiety has the formula:
R 2 is independently halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —OCX 2 3 , —OCH 2 X 2 , —OCHX 2 2 , —CN, —SO n2 R 2D , —SO v2 NR 2A R 2B , —NR 2C NR 2A R 2B , —ONR 2A R 2B , —NHC(O)NR 2C NR 2A R 2B , —NHC(O)NR 2A R 2B , —N(O) m2 , —NR 2A R 2B , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , —SF 5 , —N 3 , —NS(O)F 2 , —NS(O)FNR 2A R 2B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2A , R 2B , R 2C , and R 2D are independently hydrogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CN, —OH, —NH 2 , —COOH, —CONH 2 , —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCI 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X 2 is independently —F, —Cl, —Br, or —I;
n2 is independently an integer from 0 to 4;
m2 and v2 are independently 1 or 2;
z2 is an integer from 0 to 7; and
R 3 is:
wherein
R 16 , R 17 , and R 18 are independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CHCl 2 , —CHBr 2 , —CHF 2 , —CHl 2 , —CH 2 CI, —CH 2 Br, —CH 2 F, —CH 2 I, —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCC, —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
2 . The compound of claim 1 , wherein L 1 is L 101 -L 102 -L 103 -L 104 -L 105 -; and
L 101 , L 102 , L 103 , L 104 , and L 105 are independently a bond, —NH−, —S—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or a bioconjugate linker.
3 . The compound of claim 1 , having the formula:
wherein
R 2.1 , R 2.2 , R 2.3 , and R 2.4 are independently hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —OCX 2 3 , —OCH 2 X 2 , —OCHX 2 2 , —CN, —SO n2 R 2D , —SO v2 NR 2A R 2B , —NR 2C NR 2A R 2B , —ONR 2A R 2B , —NHC(O)NR 2C NR 2A R 2B , —NHC(O)NR 2A R 2B , —N(O) m2 , —NR 2A R 2B , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C (O) R 2C , —NR 2A C (O) OR 2C , —NR 2A OR 2C , —SF 5 , —N 3 , —NS(O)F 2 , —NS(O)FNR 2A R 2B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
4 . The compound of claim 1 , wherein R 3 is
5 . The compound of claim 1 , wherein the BRD4 binding moiety has the formula:
6 . The compound of claim 1 , wherein L 1 is
wherein p is an integer from 1 to 10.
7 . The compound of claim 1 , having the formula
wherein p is an integer from 1 to 8.
8 . The compound of claim 4 , wherein R 16 is hydrogen, R 17 is hydrogen, and R 18 is hydrogen.
9 . The compound of claim 4 , wherein R 16 is hydrogen, R 17 is hydrogen, and R 18 is unsubstituted methyl.
10 . The compound of claim 4 , wherein R 16 is hydrogen, R 17 is hydrogen, and R 18 is —CN.
11 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
12 . A method of increasing the level of a protein in a cell, wherein the level of the protein is regulated by p53, said method comprising contacting the cell with the compound of claim 1 .
13 . A method of treating a p53 Y220C mutant cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of the compound of claim 1 .
14 . A method of treating a p53 +/mut cancer, said method comprising administering to a subject in need thereof an effective amount of the compound of claim 1 to said subject.