Key binder peptides showing SAR evolution and non-binder control peptides.
| Compound | Peptide sequencea | Changes | KRASG12D GDP TR-FRET EC50 (nM) | AsPC-1 pERK EC50 1 h/18 h (μM) | AsPC-1 LDH EC50 1 h/18 h (μM) | A375 pERK EC50 1 h/18 h (μM) | NanoClick EC50 4 h/18 h (nM) |
|---|---|---|---|---|---|---|---|
| MP-6483 (binder) | Ac-K(N3)-RRRR-cyclo(c(methylene)PLYISYDPVC)-RRRR-NH2 | None | 172.4 | 15.9/>50 | >50/>50 | NT | 2693/636 |
| MP-4090 (binder) | Ac-K(N3)-rrrr-cyclo(c(methylene)PLYISYDPVC)-rrrr-NH2 | All d-Arg | 140.7 | 3.6/30.5 | >50/>50 | >50/>50 | 250.5/34.9 |
| MP-3995 (binder) | Ac-KN3)-rrrr-cyclo(c(methylene)PLYI-αMeS-YDPVC)-rrrr-NH2 | All d-Arg, Ser10α-Me-Ser | 172.1 | 1.2/1.5 | >50/>50 | >50/>50 | 1777/32.1 |
| MP-4956 (non-binder) | Ac-rrrr-cyclo(c(methylene)plyisydpvc)-rrrr-NH2 | All d-peptide | >48 080 | >50/>50 | >50/>50 | NT/>50 | NT |
| MP-9657 (non-binder) | Ac-K(N3)-rrrr-cyclo(c(methylene)PLYiSYDPVC)-rrrr-NH2 | All d-Arg, Ile9d-Ile | >48 080 | >50/>50 | >50/>50 | NT | 1756/36.2 |
| MP-9658 (non-binder) | Ac-K(N3)-rrrr-cyclo(c(methylene)PLYISYdPVC)-rrrr-NH2 | All d-Arg, Asp12d-Asp | >48 080 | >50/>50 | >50/>50 | NT/>50 | 196.1/31.4 |
a
Lower case letters represent d-amino acids. NT = not tested.