Delving into the Latest Updates on Orantinib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [4]

Target

FGFRs x PDGFR x VEGFR2

Mechanism

FGFRs antagonists(Fibroblast growth factor receptors antagonists), PDGFR antagonists(Platelet-derived growth factor receptor antagonists), VEGFR2 antagonists(Vascular endothelial growth factor receptor 2 antagonists)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Breast Cancer

Inactive Indication

Advanced Hepatocellular CarcinomaColorectal CancerHepatocellular Carcinoma+ [4]

Originator Organization

Pfizer Inc.

Active Organization

Pfizer Inc.

Taiho Pharmaceutical Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H18N2O3

InChIKeyNHFDRBXTEDBWCZ-UHFFFAOYSA-N

CAS Registry252916-29-3

Corneal neovascularization (CNV) is a major cause of blindness worldwide. However, the recent drug treatment is limited by repeated administration and low drug bioavailability. In this work, SU6668 (an inhibitor of receptor tyrosine kinases) and indocyanine green (ICG) are loaded onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and then coated with anti-VEGFR2 single chain antibody (AbVr2 scFv) genetically engineered cell membrane vesicles. The nanomedicine is delivered via eye drops, and the hyperthermia induced by laser irradiation could block the blood vessels. Meanwhile, the photothermal effect can also cause the degradation of nanomaterials and release chemotherapeutic drugs in the blocked area, thereby continuously inhibit the neovascularization. Furthermore, SU6668 could inhibit the expression of heat shock protein 70 (HSP70), promoting the cell death induced by photothermal effect. In conclusion, the combination of photothermal and chemotherapy drugs provides a novel, effective and safe approach for the treatment of CNV.

01 May 2023·Chemico-Biological Interactions

Structure-based virtual screening of chemical libraries as potential MELK inhibitors and their therapeutic evaluation against breast cancer

Article

Author: Uppal, Sheetal ; Das, Amiya ; Lather, Viney ; Prajapati, Anita ; Agarwal, Pallavi ; Karna, Amarnath ; Pandita, Deepti ; Sharma, Hitesh Kumar

New targeted therapy for triple negative breast cancer (TNBC) is an urgent need, as advanced disease responds poorly to conventional chemotherapy. Genomic and proteomic studies are currently investigating new genes and proteins as promising therapeutic targets. One of such therapeutic targets is a cell cycle regulatory kinase; Maternal Embryonic Leucine Zipper Kinase (MELK), overexpressed in TNBC and correlated with cancer development. We performed molecular docking for virtual screening of chemical libraries (phytochemicals/synthetic drugs) against MELK protein structure and identified 8 phytoconstituents (isoxanthorin, emodin, gamma-coniceine, quercetin, tenuazonic acid, isoliquiritigenin, kaempferol, and Nobiletin) and 8 synthetic drugs (tetrahydrofolic acid, alfuzosin, lansoprazole, ketorolac, ketoprofen, variolin B, orantinib, and firestein) as potential hits interacting with the active site residues of MELK based on bound poses, hydrogen bond, hydrophobic interactions and MM/GBSA binding free energies. ADME and drug-likeness prediction further identified few hits with high drug-likeness properties and were further tested for anti-tumorigenic potential. Two phytochemicals isoliquiritigenin and emodin demonstrated growth inhibitory effects on TNBC MDA-MB-231 cells while much lower effect was observed on non-tumorigenic MCF-10A mammary epithelial cells. Treatment with both molecules downregulated MELK expression, induced cell cycle arrest, accumulated DNA damage and enhanced apoptosis. The study identified isoliquiritigenin and emodin as potential MELK inhibitors and provides a basis for subsequent experimental validation and drug development against cancer.

01 Jan 2023·Frontiers in pharmacology

A new molecular subclassification and in silico predictions for diagnosis and prognosis of papillary thyroid cancer by alternative splicing profile.

Article

Author: Guo, Yanzhi ; Li, Haiyan ; Lan, Hao ; Pu, Xuemei ; Li, Menglong

Introduction: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. However, different PTC variants reveal high heterogeneity at histological, cytological, molecular and clinicopathological levels, which complicates the precise diagnosis and management of PTC. Alternative splicing (AS) has been reported to be potential cancer biomarkers and therapeutic targets. Method: Here, we aim to find a more sophisticated molecular subclassification and characterization for PTC by integrating AS profiling. Based on six differentially expressed alternative splicing (DEAS) events, a new molecular subclassification was proposed to reclassify PTC into three new groups named as Cluster0, Cluster1 and Cluster2 respectively. Results: An in silico prediction was performed for accurate recognition of new groups with the average accuracy of 91.2%. Moreover, series of analyses were implemented to explore the differences of clinicopathology, molecular and immune characteristics across them. It suggests that there are remarkable differences among them, but Cluster2 was characterized by poor prognosis, higher immune heterogeneity and more sensitive to anti-PD1 therapy. The splicing correlation networks proved the complicated regulation relationships between AS events and splicing factors (SFs). An independent prognostic indicator for PTC overall survival (OS) was established. Finally, three compounds (orantinib, tyrphostin-AG-1295 and AG-370) were discovered to be the potential therapeutic agents. Discussion: Overall, the six DEAS events are not only potential biomarkers for precise diagnosis of PTC, but also the probable prognostic predictors. This research would be expected to highlight the effect of AS events on PTC characterization and also provide new insights into refining precise subclassification and improving medical therapy for PTC patients.

100 Deals associated with Orantinib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12072

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	-	Taiho Pharmaceutical Co., Ltd.	-
Breast Cancer	Phase 2	-	Pfizer Inc.	-
Breast Cancer	Phase 1	KR	Taiho Pharmaceutical Co., Ltd.	-
Stomach Cancer	Phase 1	JP	Taiho Pharmaceutical Co., Ltd.	-
Hepatocellular Carcinoma	Discovery	CN	Taiho Pharmaceutical Co., Ltd.	01 Dec 2010
Unresectable Hepatocellular Carcinoma	Discovery	TW	Taiho Pharmaceutical Co., Ltd.	01 Dec 2010
Unresectable Hepatocellular Carcinoma	Discovery	KR	Taiho Pharmaceutical Co., Ltd.	01 Dec 2010
Unresectable Hepatocellular Carcinoma	Discovery	JP	Taiho Pharmaceutical Co., Ltd.	01 Dec 2010
Colorectal Cancer	Discovery	KR	Taiho Pharmaceutical Co., Ltd.	-
Liver Cancer	Discovery	-	Pfizer Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01465464 (ORIENTAL, CTgov)	Phase 3	Unresectable Hepatocellular Carcinoma	888	Orantinib (TSU-68) (Orantinib)	(ripjyysges) = sbychubmpo bjumojfyjt (jtpnawlnwv, relohbskga - dfscvfulxd) View more	-	07 Aug 2019
NCT01465464 (ORIENTAL, CTgov)	Phase 3	Unresectable Hepatocellular Carcinoma	888	Placebo (Placebo)	(ripjyysges) = zabijapsqb bjumojfyjt (jtpnawlnwv, fhryejkxwk - zjnrxuiaqf) View more	-	07 Aug 2019
NCT01465464 (ORIENTAL, Pubmed \| Lancet Gastroenterol Hepatol) Manual	Phase 3	Unresectable Hepatocellular Carcinoma	889	Orantinib+ cTACE+Orantinib	(mdfdwwsupx) = trhwnjumzp ukikunizpo (rbbsfpgkmp, 26.5 - 34.5) View more	Negative	01 Jan 2018
	Phase 3	Unresectable Hepatocellular Carcinoma	889	Placebo	(mdfdwwsupx) = qyeanihfsp ukikunizpo (rbbsfpgkmp, 28.4 - NR) View more	Negative	01 Jan 2018
JPRN-JapicCTI-121970 (ASCO_GI2013)	Phase 1	Advanced Hepatocellular Carcinoma	18	TSU-68 plus S-1 combination	(wgbpbnavpn) = jmqldceitc omcvtssrja (uyqwbitxas ) View more	-	01 Feb 2013
NCT00784290 (Pubmed \| Cancer Chemother Pharmacol)	Phase 1/2	Advanced Hepatocellular Carcinoma	35	TSU-68 200 mg bid	(qxoeigykiv) = avycbljnvq zbgizjgkin (cibqwslrpn ) View more	Positive	01 Feb 2011
ASCO2010	Phase 2	Hepatocellular Carcinoma	101	TSU-68 400 mg/d	(ooobgafhuu) = ejhuiouoqx yqvlrayruv (dtpzwqrenm )	-	20 May 2010
ASCO2010	Phase 2	Hepatocellular Carcinoma	101	No antitumor therapy	(ooobgafhuu) = fisahdacmr yqvlrayruv (dtpzwqrenm )	-	20 May 2010
ASCO2008	Phase 1/2	Advanced Hepatocellular Carcinoma	35	TSU-68 400 mg/d	(aqthknlond) = ompyemuzox udcqtdxvck (bkvwjwmtau ) View more	Positive	20 May 2008