Table 1.
Comparison of DMX-5804 and the Starting Compound F1386-0303
| Selectivity | |||
|---|---|---|---|
| Target | F1386-0303 pIC50 (Fold Selectivity) | DMX-5804 pIC50 (Fold Selectivity) | DMX-5804 vs F1386-0303 |
| MAP4K4 | 7.46 | 8.55 | – |
| MINK1/MAP4K6 | 7.42 | 8.18 | – |
| TNIK/MAP4K7 | 7.03 | 7.96 | – |
| GCK/MAP4K2 | 5.91 (35) | 6.50 (112) | 3.20 |
| GLK/MAP4K3 | 4.52 (871) | 4.95 (3981) | 4.57 |
| KHS/MAP4K5 | 5.22 (174) | 6.36 (153) | 0.88 |
| ABL1 | 4.52 (865) | 5.80 (560) | 0.65 |
| Aurora B | 4.88 (380) | 5.49 (560) | 1.47 |
| FLT3 | 5.66 (63) | 5.31 (1148) | 18.22 |
| GSK3β | 4.57 (776) | 4.66 (7762) | 10.00 |
| MLK1/MAP3K9 | 6.28 (15) | 7.19 (23) | 1.53 |
| MLK3/MAP3K11 | 6.09 (23) | 6.99 (36) | 1.57 |
| NUAK | 6.16 (20) | 6.88 (47) | 2.35 |
| VEGFR | 5.72 (55) | 5.72 (675) | 12.27 |
| Pharmacokinetics | |||
| Target | F1386-0303 | DMX-5804 | DMX-5804 versus F1386-0303 |
| IV PK (1 mg kg−1) | |||
| Cl (L hr−1 kg−1) | 5.33 | 2.50 | 0.47 |
| t1/2 (h) | 0.1 | 0.6 | 6.00 |
| Cmax (nM) | 3262 | 1590 | 0.49 |
| Vd (L kg−1) | 1.05 | 1.22 | 1.16 |
| Oral PK (50 mg kg−1) | |||
| AUCinf | 2162 | 63733 | 29.48 |
| Cmax (nM) | 295 | 13847 | 46.94 |
| Tmax (h) | 1.00 | 1.00 | 1.00 |
| t1/2 (h) | 3.7 | 1.8 | 0.49 |
Selectivity: the top compound from pharmacophore modeling (F1386-0303) and its derivative DMX-5804 were tested for activity against MAP4K4 and selected other human protein kinases (HTRF Transcreener ADP assay). Apart from related MAP4Ks, the kinases tested for full dose-response relations were chosen on the basis of off-target activity in the Dundee selectivity panel (Table S2). VEGFR was detected as an off-target hit of DMX-5804 at the dose used for compound screening, but is nearly 700-fold less sensitive than MAP4K4. Pharmacokinetics: plasma concentrations were determined after intravenous or oral administration at the doses shown. AUCinf, area under the plasma concentration-time curve from time 0 to infinite; Cl, clearance; Cmax, peak concentration; t1/2, plasma half-life; Tmax, time of peak concentration; Vd, volume of distribution.