Genase presents preclinical data of its DHODH inhibitor GTX-196 at AACR 2022

Oss, The Netherlands – Genase Therapeutics B.V. today announced its participation at the American Association for Cancer Research (AACR) Annual Meeting taking place from April 8-13, 2022 in New Orleans. Genase will present preclinical data on its development candidate GTX-196, a novel orally available inhibitor of dihydroorotate dehydrogenase (DHODH), a critical enzyme in de novo pyrimidine biosynthesis, for the treatment of hematologic malignancies.

Details on the presentations are as follows:

Poster #6616

Title: Preclinical pharmacology profile of GTX-0196: A novel, potent and highly selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of hematologic malignancies

Presenter: Allard Kaptein

Date & Time: Wednesday April 13 from 9:00 AM - 12:30 PM (CST)

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Abstract

Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis. Initial clinical studies with the DHODH inhibitor brequinar in solid tumors showed limited efficacy due to dose limiting adverse effects. Recently, there is renewed interest in the use of more potent and selective DHODH inhibitors for the treatment of myeloid and lymphoid malignancies.

Here we report the identification of the novel potent and highly selective DHODH inhibitor GTX-0196, with excellent physicochemical properties. GTX-0196 exhibited a biochemical IC₅₀ of 3.7 nM in a DHODH biochemical assay and an antiproliferative IC₅₀ of 1.1 nM in the MOLM-13 cell line, with brequinar showing IC₅₀ values of 6.9 and 50 nM, respectively. The activity in the MOLM-13 proliferation assay was uridine-dependent, indicating absence of general toxicity of the compound and confirming DHODH-mediated efficacy.

Profiling of GTX-0196 in the BioPrint panel (Eurofins/CEREP, at 10 µM), showed <50% inhibition for all 133 target proteins tested (GPCR’s, NR´s, kinases and other enzymes), illustrating the high selectivity for DHODH (> 2000-fold selectivity versus other targets tested). Furthermore, no inhibition was observed in a human CYP panel (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4, at 30 µM) and in a panel of transporters (at 10 µM). High metabolic stability in human liver microsomes and hepatocytes was observed with t_½ > 6h and 10h, respectively.

Compared to an earlier lead compound, GTX-0196 demonstrated enhanced potency and metabolic stability (particularly in preclinical species). Potent and efficacious inhibition of proliferation through DHODH was confirmed in a large number of solid tumor and hematologic malignancy cell lines, illustrating the broad potential use of this chemical series. Furthermore, tumor growth inhibition was observed in the MOLM-13 xenograft mouse model.

Due to its favorable properties, GTX-0196 has progressed towards IND-enabling studies. In parallel, we are exploring mono and combination therapy opportunities in hematological malignancies as well as combination therapy opportunities in solid tumors to investigate the full therapeutic potential in oncology for this optimized DHODH inhibitor.