PRPK-TPRKB modulators and uses thereof
The present invention provides methods of identifying an agent that modulates PRPK, TPRKB, OSGEP, LAGE3 and its homologs, PRPK/TPRKB complex, and/or KEOPS complex. The present invention also provides compositions of such agents and methods of treating a disease, disorder, or condition associated with PRPK, TPRKB, OSGEP, LAGE3 and its homologs family (CT antigens), PRPK/TPRKB complex, and/or KEOPS complex using such an agent or composition.
1. A method of identifying an agent that modulates a PRPK/TPRKB complex comprising:
(a) providing a PRPK/TPRKB complex comprising PRPK and TPRKB;
(b) providing a first compound and a second compound;
(c) contacting the first compound and the second compound with the PRPK/TPRKB complex; and
(d) measuring an amount of interaction between the first compound, that is competed by the second compound, and the PRPK/TPRKB complex;
wherein the second compound is a compound of formula I
wherein:
X is —C(═O)— or —CH 2 —;
R 1 , R 2 , R 3 , and R 4 are independently hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, or —N(R 5 ) 2 ;
each R 5 is independently hydrogen or C 1-6 alkyl, or two R 5 groups are taken together with the nitrogen to which they are attached to form a heterocycle;
R 6 is hydrogen, halo, benzyl, or C 1-8 alkyl;
R 7 is hydrogen, benzyl, or C 1-8 alkyl; and
R 8 , R 8′ , R 9 , and R 9′ are independently hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy.
2. The method of claim 1 , further comprising:
(e) providing a second PRPK/TPRKB complex;
(f) providing the first compound and a third compound;
(g) contacting the first compound and the third compound with the second PRPK/TPRKB complex;
(h) measuring an amount of interaction between the first compound and the second PRPK/TPRKB complex that is not competed by the third compound;
(i) comparing the amount of interaction determined in (d), with that of determined in (h); and
(j) identifying the first compound competed by the second compound but not by the third compound as an agent that modulates a PRPK/TPRKB complex.
3. The method of claim 1 , wherein the PRPK/TPRKB complex is a KEOPS complex that comprises PRPK, TPRKB, OSGEP, and LAGE3 or homologs thereof.
4. The method of claim 2 , wherein the PRPK/TPRKB complex is a KEOPS complex that comprises PRPK, TPRKB, OSGEP, and LAGE3 or homologs thereof.
5. The method of claim 2 , wherein molar ratio of (a) the first compound to (b) the second compound (b/a) is from 20 to 80.
6. The method of claim 2 , wherein the second compound is a compound selected from the group consisting of:
7. The method of claim 2 , wherein the second compound is labeled.
8. The method of claim 7 , wherein the second compound is an affinity reagent.
9. The method of claim 1 , wherein molar ratio of (a) the first compound to (b) the second compound (b/a) is from 20 to 80.
10. The method of claim 1 , wherein the second compound is a compound selected from the group consisting of:
11. The method of claim 1 , wherein the second compound is labeled.
12. The method of claim 11 , wherein the second compound is an affinity reagent.
13. The method of claim 1 , wherein the second compound is a compound selected from the group consisting of: