BELZUTIFAN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H12F3NO4S
Molecular Weight	383.342
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CS(=O)(=O)C1=CC=C(OC2=CC(=CC(F)=C2)C#N)C3=C1[C@H](O)[C@H](F)[C@@H]3F

InChI

InChIKey=LOMMPXLFBTZENJ-ZACQAIPSSA-N

InChI=1S/C17H12F3NO4S/c1-26(23,24)12-3-2-11(13-14(12)17(22)16(20)15(13)19)25-10-5-8(7-21)4-9(18)6-10/h2-6,15-17,22H,1H3/t15-,16-,17+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C17H12F3NO4S
Molecular Weight	383.342
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Belzutifan (PT2977) is an orally active, small molecule inhibitor of hypoxia-inducible factor (HIF)-2alpha (HIF-2a). Upon oral administration, HIF-2alpha inhibitor PT2977 binds to and blocks the function of HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate hypoxic signaling. This inhibits cell growth and survival of HIF-2alpha-expressing tumor cells. HIF-2alpha, the alpha subunit for the heterodimeric transcription factor HIF-2, is overexpressed in many cancers and promotes tumorigenesis.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Endothelial PAS domain-containing protein 1 7	Inhibitor 8,504		9.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Advanced solid cancer 30	Primary	Phase I 438	Unknown
Solid carcinoma 1	Primary	Phase I 438	Unknown
Clear cell adenocarcinoma 1	Primary	Phase I 438	Unknown
Renal cell carcinoma 33	Primary	Phase I 438	Unknown
Von Hippel-Lindau disease 1	Primary	Approved 8,583	WELIREG

C_max

Value	Dose	Analyte	Population
665 ng/mL	40 mg single, oral	BELZUTIFAN plasma	Homo sapiens
1.3 μg/mL	120 mg 1 times / day steady-state, oral	BELZUTIFAN plasma	Homo sapiens
172.9 ng/mL	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
572 ng/mL	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
1240.67 ng/mL	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
1346 ng/mL	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2042 ng/mL	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2540 ng/mL	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
1277 ng/mL	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
245.2 ng/mL	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
540.8 ng/mL	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
1402.5 ng/mL	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
1791.98 ng/mL	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2041.67 ng/mL	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2671.67 ng/mL	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2672 ng/mL	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
15 μg × h/mL	40 mg single, oral	BELZUTIFAN plasma	Homo sapiens
16.7 μg × h/mL	120 mg 1 times / day steady-state, oral	BELZUTIFAN plasma	Homo sapiens
1530.59 ng × h/mL	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
5396.19 ng × h/mL	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
12513 ng × h/mL	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
14559.56 ng × h/mL	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
16851.51 ng × h/mL	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
24767.93 ng × h/mL	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
8846.05 ng × h/mL	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
2170.64 ng × h/mL	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
7136.85 ng × h/mL	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
18369.47 ng × h/mL	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
21046.06 ng × h/mL	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
22271.92 ng × h/mL	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
27874.67 ng × h/mL	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
22256.03 ng × h/mL	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
14 h	120 mg 1 times / day steady-state, oral	BELZUTIFAN plasma	Homo sapiens
11.17 h	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
16.52 h	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
20.28 h	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
16.84 h	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
13.09 h	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
14.34 h	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
13.49 h	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
12.87 h	20 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
18.52 h	40 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
21.48 h	80 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
15.95 h	120 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
13.18 h	160 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
13.88 h	240 mg 1 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens
14.11 h	120 mg 2 times / day multiple, oral	BELZUTIFAN plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
55%			BELZUTIFAN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT	Disc. AE: Disease progression, Malignant neoplasm progression...
120 mg 1 times / day steady, oral Studied dose	unhealthy, ADULT	Disc. AE: Malignant neoplasm progression, Disease progression...
120 mg 1 times / day steady, oral Studied dose	unhealthy, ADULT	Disc. AE: Dizzines...

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AEs

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AE	Significance	Dose	Population
Abdominal pain	1 patient Disc. AE	240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT
Acute kidney injury	1 patient Disc. AE	240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT
Cardiac arrest	1 patient Disc. AE	240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT
Decreased appetite	1 patient Disc. AE	240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT
Disease progression	1 patient Disc. AE	240 mg 1 times / day steady, oral Highest studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 substrate 1,946 inducer 1,087	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MATE2K 17 CYP2B6 926 BCRP 910 P-gp 1,741 CYP2C19 2,057 CYP2C8 1,057 CYP1A2 2,153 OATP1B3 961 OCT2 779 CYP3A5 136 OAT1 725 MATE1 415 OAT3 747 OATP1B1 1,079	UGT2B17 237 CYP2C19 1,119 P-gp 2,052 OATP1B1 503 BCRP 697 OATP1B3 435	CYP2B6 669 CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inducer 1,966	no
CYP2B6 1,160	inhibitor 4,027	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
UGT2B17 237	substrate 4,014	major	yes (pharmacogenomic study)
CYP3A4 1,946	substrate 4,014	minor
BCRP 697	substrate 4,014	no
OATP1B1 503	substrate 4,014	weak
OATP1B3 435	substrate 4,014	weak

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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

Title	Date	PubMed
Belzutifan: First Approval.	2021 Nov	34613603
Belzutifan: A Narrative Drug Review.	2022	35366789

Patents

Substance Class	Chemical
Record UNII	7K28NB895L
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BELZUTIFAN

Official Name

English

belzutifan [INN]

Preferred Name

English

3-((1S,2S,3R)-2,3-DIFLUORO-1-HYDROXY-7-METHYLSULFONYLINDAN-4-YL)OXY-5-FLUORO-BENZONITRILE

Systematic Name

English

WELIREG

Brand Name

English

MK6482

Code

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

745820

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Code System

Code

Type

Description

FDA UNII

7K28NB895L

PRIMARY

NCI_THESAURUS

C135627

PRIMARY

RXCUI

2567226

PRIMARY

WIKIPEDIA

Belzutifan

PRIMARY

CAS

1672668-24-4

PRIMARY

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Related Record

Type

Details


					1B37H0967P

ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1

TARGET -> INHIBITOR

Comments:

Disrupts the dimerization of HIF-2a and ARNT.

Qualification:

Ki

Amount:

23 NANOMOLAR (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

52 % (average)


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> SUBSTRATE

Amount:


					W80H4WI8LW

URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASE 2B17

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR

Qualification:

Vmax

Amount:

0.0047 nM/min/mg protein (average)


					1B37H0967P

ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1

TARGET -> INHIBITOR

Comments:

Cellular luciferase assay. Compared to PT2385, found to be 2- to 3-fold more potent.

Qualification:

EC50

Amount:

11 NANOMOLAR (average)

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Related Record

Type

Details


					DF5ND8JZ4R

PT-3317

METABOLITE INACTIVE -> PARENT

Comments:

In humans, the metabolite exposure was approximately 30% of belzutifan exposure.

Interaction Type:

MAJOR

Qualification:

PLASMA

Amount:

MOLE PERCENT OF AMOUNT ABSORBED 30 % (average)

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Related Record

Type

Details


					7K28NB895L

BELZUTIFAN

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	14 hours (average)

log D	CHEMICAL	1.2 (average)

SMILES

InChI

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

C_max

T_1/2

F_unbound

Drug as perpetrator