Table 3. In Vitro Inhibition of HSET and Kinetic Aqueous Solubility Measurements of 33–39.
| compound | chirality | R5 | R6 | HSET ADP-Glo IC50 (nM)a | KSol data (μM)b |
|---|---|---|---|---|---|
| 33 | (S) | H | H | 13 (±3) | >90 |
| 34 | (R) | CH3 | H | 260 (±47) | >90 |
| 35 | (S) | CH3 | H | 19 (±7) | >90 |
| 36 | (S) | CH3 | CH3 | 11 (±4) | >90 |
| 37 | (S) | H | A | 257 (±70)c | n.d. |
| 38 | (S) | CH3 | B | 217d | 1.8 |
| 39 | (S) | CH3 | C | 107 (±24) | 53 |
| 40 | (S) | CH3 | D | 39 (±18) | 1.1 |
a
Inhibition of recombinant full-length HSET with preformed microtubules and 3 μM ATP measured in ADP-Glo format, mean (±SD) for n ≥ 3.
b
Solubility measured by HPLC with UV detection in PBS buffer at pH 7.4 (100 μM solution with 1% DMSO starting solution). The calibration curve was prepared by injecting 0.5, 2.5, and 5 μL of a 100% DMSO stock solution.
c
n = 2.
d
Single determination.