SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor

  • Eur J Med Chem. 2022 Dec 15:244:114826. doi: 10.1016/j.ejmech.2022.114826.
Ramil Y Baiazitov  1 ,  Hongyan Qi ,  Tamil Arasu  2 ,  William Lennox  3 ,  Liangxian Cao  4 ,  Marla Weetall  4 ,  Bansri Furia  5 ,  Jin Zhuo  5 ,  Soongyu Choi  6 ,  Min Jung Kim  4 ,  Josephine Sheedy  4 ,  Thomas Davis  7 ,  Young-Choon Moon  4
Affiliations
  • 1. PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA. Electronic address: [email protected].
  • 2. Lachman Consultant Services, Inc., 1600 Stewart Ave, Suite 604, Westbury, NY, 11590, USA.
  • 3. PTC USA, Hopewell, 311 Pennington Rocky Hill Rd., Pennington, NJ, 08534, USA.
  • 4. PTC USA, NJ Center of Excellence Campus, 1013 Route 202/206, Bridgewater, NJ, 08807, USA.
  • 5. PTC Therapeutics Inc, 100 Corporate Ct, South Plainfield, NJ, 07080, USA.
  • 6. Avelos Therapeutics, Inc., 21 Magokjungang 8-ro 7-gil, Gangseo-gu, Seoul, 07794, Republic of Korea.
  • 7. Recludix Pharmaceuticals, 3545 John Hopkins Blvd, Suite 150, San Diego, CA, 92121, USA.
PMID: 36242990 DOI: 10.1016/j.ejmech.2022.114826
Abstract

Dihydroorotate Dehydrogenase (DHODH) is the enzyme that catalyzes a rate-determining step during the de novo synthesis of uridine, an important source of cellular pyrimidine nucleotides. Ability to modulate the activity of this enzyme may be used to control diseases associated with rapid, out-of-control cell growth in oncology, immunology, and virology. Emvododstat (PTC299) is a tetrahydro-β-carboline DHODH inhibitor discovered through the GEMS technology (Gene Expression Modulation by Small-Molecules). Described in this paper is the lead optimization campaign that culminated in the discovery of this highly potent DHODH inhibitor.