PMID- 30469041 OWN - NLM STAT- MEDLINE DCOM- 20190207 LR - 20231005 IS - 1768-3254 (Electronic) IS - 0223-5234 (Print) IS - 0223-5234 (Linking) VI - 162 DP - 2019 Jan 15 TI - Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. PG - 455-464 LID - S0223-5234(18)30964-4 [pii] LID - 10.1016/j.ejmech.2018.11.010 [doi] AB - Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2. CI - Copyright (c) 2018 Elsevier Masson SAS. All rights reserved. FAU - Winters, Maria AU - Winters M AD - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. FAU - DuHadaway, James B AU - DuHadaway JB AD - Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA. FAU - Pham, Khoa N AU - Pham KN AD - Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States. FAU - Lewis-Ballester, Ariel AU - Lewis-Ballester A AD - Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States. FAU - Badir, Shorouk AU - Badir S AD - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. FAU - Wai, Jenny AU - Wai J AD - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. FAU - Sheikh, Eesha AU - Sheikh E AD - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. FAU - Yeh, Syun-Ru AU - Yeh SR AD - Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States. FAU - Prendergast, George C AU - Prendergast GC AD - Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA; Department of Pathology, Anatomy & Cell Biology and, Philadelphia, PA 19104, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA. Electronic address: prendergast@limr.org. FAU - Muller, Alexander J AU - Muller AJ AD - Lankenau Institute for Medical Research, 100 Lancaster Ave, Wynnewood, PA 19096, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA. Electronic address: muller@limr.org. FAU - Malachowski, William P AU - Malachowski WP AD - Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, 19010, USA. Electronic address: wmalacho@brynmawr.edu. LA - eng GR - R01 GM086482/GM/NIGMS NIH HHS/United States GR - R15 GM087291/GM/NIGMS NIH HHS/United States GR - R01 GM126297/GM/NIGMS NIH HHS/United States GR - R01 CA191191/CA/NCI NIH HHS/United States GR - R01 CA109542/CA/NCI NIH HHS/United States GR - R01 GM115773/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20181114 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antineoplastic Agents) RN - 0 (Hydroxylamines) RN - 0 (IDO1 protein, human) RN - 0 (IDO2 protein, human) RN - 0 (Immunologic Factors) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - EC 1.13.11.11 (Tryptophan Oxygenase) SB - IM MH - Animals MH - Anti-Inflammatory Agents MH - Antineoplastic Agents MH - Humans MH - Hydroxylamines/*pharmacology MH - Immunologic Factors MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/*antagonists & inhibitors MH - Tryptophan Oxygenase/*antagonists & inhibitors PMC - PMC6318801 MID - NIHMS1513180 OTO - NOTNLM OT - Antitumor therapy OT - Diaryl oalkylhydroxylamines OT - Dual inhibitor OT - IDO1 inhibition OT - IDO2 inhibition OT - Pan inhibition OT - TDO inhibition COIS- Conflict of Interest Statement AJM, WPM and GCP declare interests as inventors of IDO technology licensed to New Link Genetics Corporation, a biopharmaceutical company involved in the clinical development of IDO inhibitors, as described in U.S. Patents Nos. 7705022, 7714139, 8008281, 8058416, 8383613, 8389568, 8436151, 8476454 and 8586636. WPM and GCP are also former scientific advisors and GCP a former grants recipient of New Link Genetics. GCP is currently a scientific advisor for Kyn Therapeutics, which is developing IDO/TDO/AhR small molecule antagonists for cancer treatment. AJM is a scientific advisor and grant recipient of I-O Biotech AG, which is developing IDO vaccines for cancer treatment. EDAT- 2018/11/24 06:00 MHDA- 2019/02/08 06:00 PMCR- 2020/01/15 CRDT- 2018/11/24 06:00 PHST- 2018/08/02 00:00 [received] PHST- 2018/10/06 00:00 [revised] PHST- 2018/11/05 00:00 [accepted] PHST- 2018/11/24 06:00 [pubmed] PHST- 2019/02/08 06:00 [medline] PHST- 2018/11/24 06:00 [entrez] PHST- 2020/01/15 00:00 [pmc-release] AID - S0223-5234(18)30964-4 [pii] AID - 10.1016/j.ejmech.2018.11.010 [doi] PST - ppublish SO - Eur J Med Chem. 2019 Jan 15;162:455-464. doi: 10.1016/j.ejmech.2018.11.010. Epub 2018 Nov 14.