Inhibition of Shp2/PTPN11 protein tyrosine phosphatase by NSC-87877, NSC-117199 and their analogs
Compounds and associated methods for inhibiting a protein tyrosine phosphatase. By a combination of experimental and virtual screenings of the NCI Diversity Set chemical library, NSC-87877 and NSC-117199 have been identified as Shp2 PTP inhibitors. Significantly, NSC-87877 is active in cell-based assays and has no detectable off-target effects in the EGF-stimulated Erk 1/2 activation pathway. Additionally, a number of analogs of NSC-117199 have been produced. These analogs exhibit enhanced protein tyrosine phosphatase inhibition and are found to be potent and/or selective inhibitors of Shp1 and/or Shp2 protein tyrosine phosphatases.
1. A compound having the formula (I):
wherein R 1 is CO 2 H, SO 2 NHCH 2 (C 6 H 4 )—X, SO 2 NHCH 2 (C 6 H 5 ), SO 2 N(CH3) 2 , or SO 2 NHCH 2 (C 6 H 4 )OCH 3 ,
wherein X is one or more moieties selected from the group consisting of chlorine, oxymethyl, fluorine, methyl and morpholine;
wherein R 4 and R 5 are hydrogen;
wherein each of R 2 and R 3 are hydrogen, nitro, or CO 2 H;
R 6 is hydrogen; and
wherein one of R 2 and R 3 is hydrogen and R 2 and R 3 are not concurrently the same functional group.
2. The compound according to claim 1 wherein R 2 or R 3 is nitro.
3. A compound having the formula (II):
wherein R 1 is CO 2 H, SO 2 NHCH 2 (C 6 H 5 ), or SO 2 NHCH 2 C 6 H 4 Cl;
wherein each of R 2 and R 3 are independently hydrogen, nitro, or CO 2 H;
wherein R 4 is hydrogen, or benzyl; and
wherein one of R 2 and R 3 is hydrogen and R 2 and R 3 are not concurrently the same functional group.
4. The compound according to claim 3 wherein R 1 is SO 2 NHCH 2 C 6 H 4 Cl.
5. The compound according to claim 4 wherein R 2 is selected from the group consisting of nitro, and CO 2 H.
6. The compound according to claim 3 wherein R 4 is hydrogen.
7. A compound having the formula (III):
wherein each of R 1 through R 5 are independently hydrogen, nitro, or CO 2 H;
R 6 is hydrogen; and
R 7 is NHCH 2 (C 6 H 4 )—X,
wherein X is one or more moieties selected from the group consisting of hydrogen, fluorine, chlorine, and oxymethyl;
wherein at least one of R 1 through R 5 is not hydrogen.
8. The compound according to claim 7 wherein R 3 through R 6 are hydrogen and each of R 1 and R 2 is selected from the group consisting of nitro and CO 2 H.
9. A compound having the formula (IV):
wherein each of R 1 and R 2 are independently hydrogen, nitro, CO 2 H, or CO 2 CH 3 ;
R 3 through R 5 are hydrogen;
R 6 is hydrogen;
R 7 is NHCH 2 (C 6 H 4 )—X, SO 2 NHCH 2 (C 6 H 5 ); or SO 2 NHCH 2 (C 6 H 4 )OCH 3 ;
wherein X is one or more moieties selected from the group consisting of chlorine, and oxymethyl; and
wherein at least one of R 1 through R 5 is not hydrogen.
10. The compound according to claim 1 wherein R 2 is nitro when R 1 is SO 2 NHCH 2 (C 6 H 4 )—X, SO 2 NHCH 2 (C 6 H 5 ), SO 2 N(CH 3 ) 2 , or SO 2 NHCH 2 (C 6 H 4 )OCH 3 .
11. The compound according to claim 3 wherein R 2 is nitro when R 1 is SO 2 NHCH 2 (C 6 H 5 ), or SO 2 NHCH 2 C 6 H 4 Cl.