fig10

Figure 10. A: Superimposition of the binding mode of compound 2a (PDB ID: 4WNO) and compound 2b (PDB ID: 4WNP) in ULK1; B: binding mode of compound 2c (PDB ID: 5CI7) in ULK1. Hydrogen bond interactions are represented in black dotted lines. Compound 2c with a diaminopropyl group, a closely related pyrimidine analog of MRT67307, showed dose dependent inhibition with an IC50 of 120 nmol/L. Co-crystallization of compound 2c with ULK1 [Figure 10B] showed that it has similar orientation with the diaminopropyl group occupying a similar space as that of quinazoline of compound 2a. The main difference in the kinase is the movement in the β sheet in the N-terminal lobe with Gly23 towards the inhibitor, which allows Ile22 to twist away from the bulky diaminopropyl substituent on the pyrimidine. The other difference is the gatekeeper methionine moves towards iodine group, to adopt a suitable dipole-dipole interaction. A flexible region involving Ile22 was required to pack above the aminopropyl group^[78]