Discovery of Nanomolar Inhibitors for Human Dihydroorotate Dehydrogenase Using Structure-Based Drug Discovery Methods

We used a structure-based drug discovery approach to
identify novel
inhibitors of human dihydroorotate dehydrogenase (DHODH), which is
a therapeutic target for treating cancer and autoimmune and inflammatory
diseases. In the case of acute myeloid leukemia, no previously discovered
DHODH inhibitors have yet succeeded in this clinical application.
Thus, there remains a strong need for new inhibitors that could be
used as alternatives to the current standard-of-care. Our goal was
to identify novel inhibitors of DHODH. We implemented prefiltering
steps to omit PAINS and Lipinski violators at the earliest stages
of this project. This enriched compounds in the data set that had
a higher potential of favorable oral druggability. Guided by Glide
SP docking scores, we found 20 structurally unique compounds from
the ChemBridge EXPRESS-pick library that inhibited DHODH with IC50, DHODH values between 91 nM and 2.7 μM. Ten of
these compounds reduced MOLM-13 cell viability with IC50, MOLM‑13 values between 2.3 and 50.6 μM. Compound 16 (IC50, DHODH = 91 nM) inhibited DHODH more potently than
the known DHODH inhibitor, teriflunomide (IC50, DHODH = 130 nM), during biochemical characterizations and presented a
promising scaffold for future hit-to-lead optimization efforts. Compound 17 (IC50, MOLM‑13 = 2.3 μM) was
most successful at reducing survival in MOLM-13 cell lines compared
with our other hits. The discovered compounds represent excellent
starting points for the development and optimization of novel DHODH
inhibitors.