ONC212

• CAT Number: I011869
• CAS Number: 1807861-48-8
• Molecular Formula: C24 H23 F3 N4 O
• Molecular Weight: 440.46
• Purity: ≥95%
• Storage: RT

ONC212 (CAT: I011869) is a small molecule compound that has gained attention for its potential as an anticancer agent. It belongs to the family of imipridones, which are synthetic compounds with diverse biological activities. ONC212 exerts its anticancer effects through multiple mechanisms, including induction of apoptosis, inhibition of mitochondrial respiration, and suppression of signaling pathways such as AKT and ERK. It has shown promising activity against a wide range of cancer types, including solid tumors and hematological malignancies, both in vitro and in animal models. ONC212 has the potential to be developed as a targeted therapy for cancer treatment.

Reference

1. Cell Cycle. 2017 Oct 2;16(19):1790-1799. doi: 10.1080/15384101.2017.1325046. Epub
2017 May 10.

Preclinical evaluation of the imipridone family, analogs of clinical stage
anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212.

Wagner J(1), Kline CL(1), Ralff MD(1), Lev A(1), Lulla A(1), Zhou L(1), Olson
GL(2), Nallaganchu BR(2), Benes CH(3), Allen JE(4), Prabhu VV(4), Stogniew M(4),
Oster W(4), El-Deiry WS(1).

Author information:
(1)a Laboratory of Translational Oncology and Experimental Cancer Therapeutics,
Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase
Cancer Center , Philadelphia , PA , USA.
(2)b Provid Pharmaceuticals, Monmouth Junction , NJ , USA.
(3)c Massachusettes General Hospital , Boston , MA , USA.
(4)d Oncoceutics, Inc. , Philadelphia , PA , USA.

Anti-cancer small molecule ONC201 upregulates the integrated stress response
(ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene
activation. ONC201 is under investigation in multiple clinical trials to treat
patients with cancer. Given the unique imipridone core chemical structure of
ONC201, we synthesized a series of analogs to identify additional compounds with
distinct therapeutic properties. Several imipridones with a broad range of in
vitro potencies were identified in an exploration of chemical derivatives. Based
on in vitro potency in human cancer cell lines and lack of toxicity to normal
human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further
study. Both analogs inhibited colony formation, and induced apoptosis and
downstream signaling that involves the integrated stress response and Akt/ERK,
similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of
cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was
further tested in >1000 human cancer cell lines in vitro and evaluated for safety
and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at
nanomolar concentrations across solid tumors and hematological malignancies. Skin
cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally
administered ONC212 displayed potent anti-tumor effects in vivo, a broad
therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in
BRAF V600E melanoma models that are less sensitive to ONC201. Based on these
findings, ONC212 warrants further development as a drug candidate. It is clear
that therapeutic utility extends beyond ONC201 to include additional imipridones.

2. Oncotarget. 2017 Sep 12;8(47):81776-81793. doi: 10.18632/oncotarget.20819.
eCollection 2017 Oct 10.

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response
(UPR) and is reduced by IGF1-R and GRP78/BIP.

Lev A(1), Lulla AR(1), Wagner J(1), Ralff MD(1), Kiehl JB(1), Zhou Y(2), Benes
CH(3), Prabhu VV(4), Oster W(4), Astsaturov I(5), Dicker DT(1), El-Deiry WS(1).

Author information:
(1)Department of Hematology/Oncology, Laboratory of Translational Oncology and
Experimental Cancer Therapeutics, Molecular Therapeutics Program, Fox Chase
Cancer Center, Philadelphia, PA, USA.
(2)Biostatistics Department, Fox Chase Cancer Center, Philadelphia, PA, USA.
(3)Massachusetts General Hospital, Boston, MA, USA.
(4)Oncoceutics, Inc., Philadelphia, PA, USA.
(5)Department of Hematology/Oncology, Molecular Therapeutics Program, Fox Chase
Cancer Center, Philadelphia, PA, USA.

Pancreatic cancer is chemo-resistant and metastasizes early with an overall
five-year survival of ～8.2%. First-in-class imipridone ONC201 is a small molecule
in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201
analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer
models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer
cell lines (N=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4
in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic
cancer as single agent or in combination with 5-fluorouracil, irinotecan,
oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival
IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor
AG1024, including in vivo. We show a rationale for targeting pancreatic cancer
using ONC212 combined with targeting the unfolded-protein response and ER
chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones,
anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.