UMBRALISIB TOSYLATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C31H24F3N5O3.C7H8O3S
Molecular Weight	743.751
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC1=CC=C(C=C1)S(O)(=O)=O.CC(C)OC2=C(F)C=C(C=C2)C3=NN([C@@H](C)C4=C(C5=CC=CC(F)=C5)C(=O)C6=CC(F)=CC=C6O4)C7=C3C(N)=NC=N7

InChI

InChIKey=KYJWUPZPSXZEPG-NTISSMGPSA-N

InChI=1S/C31H24F3N5O3.C7H8O3S/c1-15(2)41-24-9-7-18(12-22(24)34)27-26-30(35)36-14-37-31(26)39(38-27)16(3)29-25(17-5-4-6-19(32)11-17)28(40)21-13-20(33)8-10-23(21)42-29;1-6-2-4-7(5-3-6)11(8,9)10/h4-16H,1-3H3,(H2,35,36,37);2-5H,1H3,(H,8,9,10)/t16-;/m0./s1

HIDE SMILES / InChI

Molecular Formula	C31H24F3N5O3
Molecular Weight	571.5492
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	C7H8O3S
Molecular Weight	172.202
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Umbralisib (Ukoniq, TG Therapeutics) is an orally available PI3K delta inhibitor, targeting the delta isoform with nanomolar potency and several fold selectivity over the alpha, beta, and gamma isoforms of PI3K. The delta isoform of PI3K is strongly expressed in cells of hematopoietic origin and is believed to be important in the proliferation and survival of B-cell lymphocytes. On February 5, 2021, the Food and Drug Administration granted accelerated approval to umbralisib for the following indications: adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen; adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy. However, on June 1, 2022, the FDA withdrew its approval for the cancer medicine Ukoniq due to safety concerns.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform 9	Inhibitor 8,504		6.2 nM [Kd]
Casein kinase I isoform epsilon 2	Inhibitor 8,504		180.0 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Relapsed or refractory marginal zone lymphoma 2	Primary		Withdrawn
Relapsed or refractory follicular lymphoma 4	Primary		Withdrawn

C_max

Value	Dose	Analyte	Population
1830 ng/mL	800 mg single, oral	UMBRALISIB plasma	Homo sapiens
750 ng/mL	400 mg single, oral	UMBRALISIB plasma	Homo sapiens
1680 ng/mL	1000 mg single, oral	UMBRALISIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
14200 ng × h/mL	800 mg single, oral	UMBRALISIB plasma	Homo sapiens
8830 ng × h/mL	400 mg single, oral	UMBRALISIB plasma	Homo sapiens
20700 ng × h/mL	1000 mg single, oral	UMBRALISIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
110 h	800 mg single, oral		UMBRALISIB plasma	Homo sapiens
91 h	800 mg single, oral		UMBRALISIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.2%			UMBRALISIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Diarrhea, Vomiting... Other AEs: Death, Colitis...
800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Death, Diarrhea... Other AEs: Sepsis, Colitis...

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AEs

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AE	Significance	Dose	Population
Colitis		800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT
Neutropenia	5% Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT
Transaminase increased	5% Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT
Upper respiratory tract infection	grade 3-4, <1% Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT
Vomiting	grade 3-4, <1% Disc. AE	800 mg 1 times / day multiple, oral Recommended	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252	substrate 1,193 inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,741 CYPs 29 CYP2C8 1,057 CYP1A2 2,153 CYP2B6 926 CYP2C19 2,057	MATE1 182 OCT2 434 CYP3A 220 BCRP 697 MATE2-K 33 OAT3 391 CYP1A2 1,197 P-gp 2,052 OATP1B1 503 OATP1B3 435 OAT1 395

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYPs 35	inhibitor 4,027		no (co-administration study)
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inhibitor 4,027	no
CYP2D6 2,546	inhibitor 4,027	no
P-gp 1,932	inhibitor 4,027	no	no (co-administration study)

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Drug as victim

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Target	Modality	Activity
BCRP 697	substrate 4,014	no
MATE1 182	substrate 4,014	no
MATE2-K 33	substrate 4,014	no
OAT1 395	substrate 4,014	no
OAT3 391	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

PubMed

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Title	Date	PubMed
Can umbralisib bring PI3Kδ out of the shadows?	2018 Apr	29475725
Umbralisib Inhibits PI3Kδ with Less Toxicity Than Previous Inhibitors.	2018 Apr	29500299
Umbralisib: Treatment for a Rare Lymphoma?	2019 Jun	30936084

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Sample Use Guides

In Vivo Use Guide

Relapsed or refractory marginal zone lymphoma or relapsed or refractory follicular lymphoma: recommended dosage: 800 mg orally once daily with food

Route of Administration: Oral

In Vitro Use Guide

Umbralisib (TGR-1202), a novel, next generation PI3Kδ inhibitor, inhibits PI3Kδ activity in enzyme and cell based assays with IC50 and EC50 values of 22.2 & 24.3 nM, respectively.

Substance Class	Chemical
Record UNII	FU8XW5V3FS
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

UMBRALISIB TOSYLATE

Common Name

English

4H-1-BENZOPYRAN-4-ONE, 2-((1S)-1-(4-AMINO-3-(3-FLUORO-4-(1-METHYLETHOXY)PHENYL)-1H-PYRAZOLO(3,4-D)PYRIMIDIN-1-YL)ETHYL)-6-FLUORO-3-(3-FLUOROPHENYL)-,4-METHYLBENZENESULFONATE

Preferred Name

English

UKONIQ

Brand Name

English

UMBRALISIB TOSYLATE [ORANGE BOOK]

Common Name

English

UMBRALISIB TOSYLATE [USAN]

Common Name

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Angiogenesis Inhibitor

NCI_THESAURUS

C2152

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Code System

Code

Type

Description

USAN

CD-145

PRIMARY

CAS

1532533-72-4

PRIMARY

ChEMBL

CHEMBL3545267

PRIMARY

PUBCHEM

86707828

PRIMARY

DAILYMED

FU8XW5V3FS

PRIMARY

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Details


					38073MQB2A

UMBRALISIB

PARENT -> SALT/SOLVATE

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					38073MQB2A

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ACTIVE MOIETY

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator