Discovery and clinical introduction of first-in-class imipridone ONC201.
ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.
Oncoceutics, Inc., Philadelphia, PA, USA.
Joshua E
JE
Allen
Fox Chase Cancer Center, Philadelphia, PA, USA.
C Leah B
CL
Kline
Oncoceutics, Inc., Philadelphia, PA, USA.
Varun V
VV
Prabhu
Fox Chase Cancer Center, Philadelphia, PA, USA.
Jessica
J
Wagner
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jo
J
Ishizawa
Weill Cornell Medicine, New York, NY, USA.
Neel
N
Madhukar
Fox Chase Cancer Center, Philadelphia, PA, USA.
Avital
A
Lev
Fox Chase Cancer Center, Philadelphia, PA, USA.
Marie
M
Baumeister
Fox Chase Cancer Center, Philadelphia, PA, USA.
Lanlan
L
Zhou
Fox Chase Cancer Center, Philadelphia, PA, USA.
Amriti
A
Lulla
Oncoceutics, Inc., Philadelphia, PA, USA.
Martin
M
Stogniew
Oncoceutics, Inc., Philadelphia, PA, USA.
Lee
L
Schalop
Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Cyril
C
Benes
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Howard L
HL
Kaufman
Provid Pharmaceuticals, Monmouth Junction, NJ, USA.
Richard S
RS
Pottorf
Provid Pharmaceuticals, Monmouth Junction, NJ, USA.
B Rao
BR
Nallaganchu
Provid Pharmaceuticals, Monmouth Junction, NJ, USA.
Gary L
GL
Olson
Kuwait University Medical School, Kuwait.
Fahd
F
Al-Mulla
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Madeleine
M
Duvic
Karmanos Cancer Institute, Detroit, MI, USA.
Gen Sheng
GS
Wu
Fox Chase Cancer Center, Philadelphia, PA, USA.
David T
DT
Dicker
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Mala K
MK
Talekar
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bora
B
Lim
Weill Cornell Medicine, New York, NY, USA.
Olivier
O
Elemento
Oncoceutics, Inc., Philadelphia, PA, USA.
Wolfgang
W
Oster
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Joseph
J
Bertino
Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Keith
K
Flaherty
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael L
ML
Wang
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gautam
G
Borthakur
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael
M
Andreeff
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Mark
M
Stein
Fox Chase Cancer Center, Philadelphia, PA, USA.
Wafik S
WS
El-Deiry
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles; D009369:Neoplasms / Q000188:drug therapy*; D011725:Pyridines; D011743:Pyrimidines
D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; C585684:TIC10 compound
ATF4; DRD2; ONC201; TIC10; integrated stress response