RIGOSERTIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H25NO8S
Molecular Weight	451.49
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC(OC)=C(\C=C\S(=O)(=O)CC2=CC=C(OC)C(NCC(O)=O)=C2)C(OC)=C1

InChI

InChIKey=OWBFCJROIKNMGD-BQYQJAHWSA-N

InChI=1S/C21H25NO8S/c1-27-15-10-19(29-3)16(20(11-15)30-4)7-8-31(25,26)13-14-5-6-18(28-2)17(9-14)22-12-21(23)24/h5-11,22H,12-13H2,1-4H3,(H,23,24)/b8-7+

HIDE SMILES / InChI

Description
Sources: http://www.businesswire.com/news/home/20111210005027/en/Onconova-Present-Data-Demonstrating-Survival-Benefit-MDS | http://www.symbiopharma.com/pipeline_e/03.html
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/15766665 | http://www.onconova.com/pipeline/#tab-id-2

Rigosertib sodium (ON 01910.Na) is a small molecule inhibitor of critical pathways important in the growth and survival of cancer cells, being developed by Onconova Therapeutics ("Onconova") for the treatment of hematologic malignancies and solid tumors. Rigosertib (ON-01910) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM in a cell-free assay. It shows 30-fold greater selectivity against Plk2 and no activity to Plk3. Extensive Phase I and Phase II studies with rigosertib have been conducted at leading institutions in the U.S. and abroad in more than 450 patients with solid tumors and hematological cancers, including MDS and AML. MDS and AML are blood disorders widely recognized as difficult to manage, with limited therapeutic options available for patients, especially those with drug-resistant disease. The multi-site Phase III ONTIME trial in MDS patients is under a Special Protocol Assessment (SPA) from the U.S. FDA and is being supported by an award from the Therapeutics Acceleration Program (TAP) of the Leukemia and Lymphoma Society (LLS). FDA has granted Orphan Drug Designation for the use of rigosertib in MDS. The clinical program in solid tumors is also advancing with initiation of the Phase II/III combination ONTRAC trial (ON 01910.Na TRial in Patients with Advanced Pancreatic Cancer) and Phase II single agent trial in ovarian cancer. In Japan, SymBio is developing rigosertib for the treatment of refractory/relapsed HR-MDS (IV form) and first-line LR-MDS (oral form).

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase PLK1 14 Target ID: CHEMBL3024 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15766665	Inhibitor 8297		9.0 nM [IC50]
phosphatidylinositol 3-kinase signaling 3 Target ID: GO:0014065 Sources: http://www.onconova.com/pipeline/#tab-id-2 \| https://www.ncbi.nlm.nih.gov/pubmed/19198627 \| https://www.ncbi.nlm.nih.gov/pubmed/24493827	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Chronic myelomonocytic leukemia 5 Sources: https://clinicaltrials.gov/ct2/show/NCT01928537 http://adisinsight.springer.com/drugs/800021213	Primary	Phase III 656	Unknown Approved Use Unknown
Myelodysplastic syndromes 58 Sources: https://clinicaltrials.gov/ct2/show/NCT01928537 http://adisinsight.springer.com/drugs/800021213	Primary	Phase III 656	Unknown Approved Use Unknown
Metastatic pancreatic adenocarcinoma 5 Sources: https://clinicaltrials.gov/ct2/show/NCT01360853	Primary	Phase III 656	Unknown Approved Use Unknown
Refractory anemia with excess blasts 2 Sources: https://clinicaltrials.gov/ct2/show/NCT01928537	Primary	Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
248 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	3200 mg 2 times / week steady-state, intravenous dose: 3200 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.93 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day multiple, oral dose: 700 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.34 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.54 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.04 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day multiple, oral dose: 560 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
210 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	4000 mg 2 times / week multiple, intravenous dose: 4000 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
976 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	3200 mg 2 times / week steady-state, intravenous dose: 3200 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
19.58 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day multiple, oral dose: 700 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.96 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
6.99 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9.32 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day multiple, oral dose: 560 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
997 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	4000 mg 2 times / week multiple, intravenous dose: 4000 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
2.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	3200 mg 2 times / week steady-state, intravenous dose: 3200 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.09 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day multiple, oral dose: 700 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.99 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	700 mg 2 times / day steady-state, oral dose: 700 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.03 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.42 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24493827	560 mg 2 times / day multiple, oral dose: 560 mg route of administration: Oral experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24947095	4000 mg 2 times / week multiple, intravenous dose: 4000 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	RIGOSERTIB SODIUM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.3% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19466411	unknown, unknown		RIGOSERTIB SODIUM plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
4200 mg 2 times / week steady-state, intravenous Highest studied dose Dose: 4200 mg, 2 times / week Route: intravenous Route: steady-state Dose: 4200 mg, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44	unhealthy, ADULT n = 1 Health Status: unhealthy Condition: gastric carcinoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44	DLT: Asphyxia, Hyponatraemia... Dose limiting toxicities: Asphyxia (grade 5, 100%) Hyponatraemia (grade 3, 100%) Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44
700 mg 2 times / day multiple, oral Highest studied dose Dose: 700 mg, 2 times / day Route: oral Route: multiple Dose: 700 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: myelodysplastic syndrome Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	DLT: Dysuria, Shortness of breath... Dose limiting toxicities: Dysuria (grade 3, 16.7%) Shortness of breath (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15
700 mg 2 times / day multiple, oral Highest studied dose Dose: 700 mg, 2 times / day Route: oral Route: multiple Dose: 700 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	DLT: Hematuria... Dose limiting toxicities: Hematuria (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17
3200 mg 2 times / week steady-state, intravenous MTD Dose: 3200 mg, 2 times / week Route: intravenous Route: steady-state Dose: 3200 mg, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.41, 44	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.41, 44	DLT: Hepatic encephalopathy... Dose limiting toxicities: Hepatic encephalopathy (grade 5, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.41, 44
560 mg 2 times / day multiple, oral MTD Dose: 560 mg, 2 times / day Route: oral Route: multiple Dose: 560 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	unhealthy, ADULT n = 24 Health Status: unhealthy Condition: myelodysplastic syndrome Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 24 Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15
560 mg 2 times / day multiple, oral MTD Dose: 560 mg, 2 times / day Route: oral Route: multiple Dose: 560 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	unhealthy, ADULT n = 33 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	DLT: Dysuria, Hematuria... Dose limiting toxicities: Dysuria (grade 3, 6%) Hematuria (grade 3, 3%) Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17

AEs

AE	Significance	Dose	Population
Hyponatraemia	grade 3, 100% DLT, Disc. AE	4200 mg 2 times / week steady-state, intravenous Highest studied dose Dose: 4200 mg, 2 times / week Route: intravenous Route: steady-state Dose: 4200 mg, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44	unhealthy, ADULT n = 1 Health Status: unhealthy Condition: gastric carcinoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44
Asphyxia	grade 5, 100% DLT, Disc. AE	4200 mg 2 times / week steady-state, intravenous Highest studied dose Dose: 4200 mg, 2 times / week Route: intravenous Route: steady-state Dose: 4200 mg, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44	unhealthy, ADULT n = 1 Health Status: unhealthy Condition: gastric carcinoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.44
Dysuria	grade 3, 16.7% DLT	700 mg 2 times / day multiple, oral Highest studied dose Dose: 700 mg, 2 times / day Route: oral Route: multiple Dose: 700 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: myelodysplastic syndrome Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15
Shortness of breath	grade 3, 16.7% DLT	700 mg 2 times / day multiple, oral Highest studied dose Dose: 700 mg, 2 times / day Route: oral Route: multiple Dose: 700 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: myelodysplastic syndrome Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/23789936 Page: p.6, 7, 15
Hematuria	grade 3, 16.7% DLT, Disc. AE	700 mg 2 times / day multiple, oral Highest studied dose Dose: 700 mg, 2 times / day Route: oral Route: multiple Dose: 700 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17
Hepatic encephalopathy	grade 5, 25% DLT, Disc. AE	3200 mg 2 times / week steady-state, intravenous MTD Dose: 3200 mg, 2 times / week Route: intravenous Route: steady-state Dose: 3200 mg, 2 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.41, 44	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/24947095 Page: p.41, 44
Hematuria	grade 3, 3% DLT	560 mg 2 times / day multiple, oral MTD Dose: 560 mg, 2 times / day Route: oral Route: multiple Dose: 560 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	unhealthy, ADULT n = 33 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17
Dysuria	grade 3, 6% DLT	560 mg 2 times / day multiple, oral MTD Dose: 560 mg, 2 times / day Route: oral Route: multiple Dose: 560 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17	unhealthy, ADULT n = 33 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/24493827 Page: p.17

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461	P-gp 1537 rMRP2 2 MRP1 107

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006419	yes [IC50 0.2635 uM]

Drug as victim

Target	Modality	Activity
rMRP2 2	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23738723/	likely
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/22678771/ \| https://cancerres.aacrjournals.org/content/66/8_Supplement/1106.2	no
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23738723/	yes

PubMed

Title	Date	PubMed
Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity.	2011 Sep 22	21812421

Patents

Sample Use Guides

In Vivo Use Guide

Rigosertib sodium will be administered as a 72-hr continuous intravenous infusion consisting of 3 consecutive doses of 1800 mg over 24 hours on Days 1, 2, and 3 of a 14-day cycle for the first 8 cycles and then on Days 1, 2, and 3 of a 28-day cycle for the following cycles.

Route of Administration: Intravenous

In Vitro Use Guide

Rigosertib sodium shows cell killing activity against 94 different tumor cell lines with IC50 of 50-250 nM, including BT27, MCF-7, DU145, PC3, U87, A549, H187, RF1, HCT15, SW480, and KB cells. In HeLa cells, Rigosertib sodium (100-250 nM) induces spindle abnormalities and apoptosis.

Name

Type

Language

RIGOSERTIB

Official Name

English

rigosertib [INN]

Common Name

English

Rigosertib [WHO-DD]

Common Name

English

N-[2-Methoxy-5-({[(1E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)phenyl]glycine

Systematic Name

English

ON01910

Code

English

RIGOSERTIB [USAN]

Common Name

English

ON-01910

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

333611