New Inhibitors of Indoleamine 2,3-Dioxygenase 1: Molecular Modeling Studies, Synthesis, and Biological Evaluation.
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive target for anticancer therapy. Herein, we report a virtual screening study which led to the identification of compound 5 as a new IDO1 inhibitor. In order to improve the biological activity of the identified hit, arylthioindoles 6-30 were synthesized and tested. Among these, derivative 21 exhibited an IC50value of 7 μM, being the most active compound of the series. Furthermore, compounds 5 and 21 induced a dose-dependent growth inhibition in IDO1 expressing cancer cell lines HTC116 and HT29. Three-dimensional quantitative structure-activity relationship studies were carried out in order to rationalize obtained results and suggest new chemical modifications.
Antonio
A
Coluccia
Sara
S
Passacantilli
Valeria
V
Famiglini
Manuela
M
Sabatino
Alchemical Dynamics s.r.l. , Piazzale Aldo Moro 5, I-00185 Rome, Italy.
Alexandros
A
Patsilinakos
Alchemical Dynamics s.r.l. , Piazzale Aldo Moro 5, I-00185 Rome, Italy.
Rino
R
Ragno
Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata (CROB) , Via Padre Pio 1, I-85028 Rionero in Vulture, Italy.
Carmela
C
Mazzoccoli
Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata (CROB) , Via Padre Pio 1, I-85028 Rionero in Vulture, Italy.
Lorenza
L
Sisinni
National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology 35 Gengo, Morioka, Obu, Aichi 474-8511, Japan.
Alato
A
Okuno
National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology 35 Gengo, Morioka, Obu, Aichi 474-8511, Japan.
Osamu
O
Takikawa
Romano
R
Silvestri
Giuseppe
G
La Regina
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase