1. Hit2lead by example: Checkpoint kinase inhibitor
Discovery of a novel class of triazolones as Checkpoint Kinase inhibitors—Hit to lead exploration
(AstraZeneca). DOI: 10.1016/j.bmcl.2010.07.015. PDB: 2BXD, 2BXI, 2BXE.
Checkpoint kinase (ChK) is a protein kinase that is activated in response to DNA
damage and is involved in cell cycle arrest. This target is higly perspective as drug
target for curing the cancer disease (esp. breast cancer, Li-Fraumeni syndrome
and other type of cancers).

2. Hit2lead by example: Checkpoint kinase inhibitor
Discovery of a novel class of triazolones as Checkpoint Kinase inhibitors—Hit to lead exploration
(AstraZeneca). DOI: 10.1016/j.bmcl.2010.07.015. PDB: 2BXD, 2BXI, 2BXE.
Hit, R = H
It was found that hit is selective to the Checkpoint kinase
(ChK) among the others found by HTS.
Synthesis of the derivates
was made to fill the so-
called sugar pocket.
PDB: 2BXD

3. Hit2lead by example: Checkpoint kinase inhibitor
4a 4b
4a and 4b analogues
filled the sugar pocket.
190 nM
10 nM
PDB: 2BXI

4. Hit2lead by example: Checkpoint kinase inhibitor
6,
10 nM
5,
520
nM
3,
800 nM
4a,
190
nM
4b,
10 nM
Filling the
“sugar”
pocket
Further modifications -
search for the more
active compounds
All compounds inactive
in intercellular assays

5. Hit2lead by example: Checkpoint kinase inhibitor
21,
9 nM
27,
690 nM
26,
10 nM
25,
40 nM
All compounds inactive
in intercellular assays
14 nM (IC50)
Active in cellular assay -
100 uM (EC50)
28

6. Hit2lead by example: Checkpoint kinase inhibitor
Superposition of the ligands from the
three PDB structures. The resultant
derivate binds in different way but
forms almost the same pattern of
hydrogen bonds.
PDB: 2BXE