Design, Synthesis, and Biological Evaluation of a Novel Series of Teriflunomide Derivatives as Potent Human Dihydroorotate Dehydrogenase Inhibitors for Malignancy Treatment

Abstract

Human dihydroorotate dehydrogenase (hDHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as hDHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited hDHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t. Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of hDHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

Tumor biomarkers for diagnosis, prognosis and targeted therapy

“…To date, classical DHODH inhibitors, such as leflunomide and teriflunomide, and several novel hDHODH inhibitors, such as brequinar, ASLAN003, BAY2402234, AG-636, PTC299, and JNJ-74856665 (NCT04609826), have been evaluated in clinical trials to investigate their safety and antitumor efficacy. 1306 …”

A novel and potent dihydroorotate dehydrogenase inhibitor suppresses the proliferation of colorectal cancer by inducing mitochondrial dysfunction and DNA damage

“…M62 was synthesized as described in our previous study and was purified to >99% purity as determined by ultraperformance liquid chromatography. 16 For in vitro assays, M62 was dissolved in dimethyl sulfoxide (10 mM), and its final concentration was no more than 0.1% (vol/vol) after addition to cells. For in vivo animal experiments, M62 was suspended in 5% DMSO, 10% PEG300, and 85% water.…”

“…A series of novel compound derivatives of TFN against DHODH was synthesized by our group and obtained M62 (compound 13u) 16 as one of the most potent and superior compounds with an IC 50 value of 6.9 nM against DHODH (Figure 1A). In addition, M62 presents slow absorptions with Tmax values of 12 h, exhibits a suitable half‐life (8.7 h) and acceptable oral bioavailability (32.8%), indicating its potential value for research in depth 16 . In our study, we measured the anti‐CRC effects of M62 and explored the underlying mechanism.…”

“…In addition, M62 presents slow absorptions with Tmax values of 12 h, exhibits a suitable half-life (8.7 h) and acceptable oral bioavailability (32.8%), indicating its potential value for research in depth. 16 In our study, we measured the anti-CRC effects of M62 and explored the underlying mechanism. The results showed that M62 significantly inhibited the growth of CRC cells both in vitro and in vivo and was well tolerated.…”

Discovery a series of novel inhibitors of human dihydroorotate dehydrogenase: Biological activity evaluation and molecular docking

“…h DHODH inhibitors can effectively reduce the activity and quantity of immune activated T lymphocytes and B lymphocytes. Therefore, they can be successfully developed as therapeutic drugs for various autoimmune diseases such as rheumatoid arthritis, cancer, organ transplant rejection, and psoriasis (Amos et al., 2023; Fox et al., 2022; Li et al., 2021; Lolli et al., 2018; Sainas et al., 2022).…”