ALECTINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H34N4O2
Molecular Weight	482.6166
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCC1=C(C=C2C(=C1)C(=O)C3=C(NC4=C3C=CC(=C4)C#N)C2(C)C)N5CCC(CC5)N6CCOCC6

InChI

InChIKey=KDGFLJKFZUIJMX-UHFFFAOYSA-N

InChI=1S/C30H34N4O2/c1-4-20-16-23-24(17-26(20)34-9-7-21(8-10-34)33-11-13-36-14-12-33)30(2,3)29-27(28(23)35)22-6-5-19(18-31)15-25(22)32-29/h5-6,15-17,21,32H,4,7-14H2,1-3H3

HIDE SMILES / InChI

Molecular Formula	C30H34N4O2
Molecular Weight	482.6166
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

Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group. Alectinib is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Approved under accelerated approval in 2015, alectinib is indicated for use in patients who have progressed on or were not tolerant of crizotinib, which is associated with the development of resistance. Alectinib is marketed as Alecensa.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ALK tyrosine kinase receptor 25	Inhibitor 8,297		1.9 nM [IC50]
SNU-2535 2	Inhibitor 8,297		33.1 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer 2	Primary		Approved 8,429	Alecensa

C_max

Value	Dose	Analyte	Population
181 ng/mL	600 mg single, oral	ALECTINIB plasma	Homo sapiens
665 ng/mL	600 mg 2 times / day multiple, oral	ALECTINIB unknown	Homo sapiens
255 ng/mL	600 mg single, oral	ALECTINIB plasma	Homo sapiens
861 ng/mL	600 mg 2 times / day steady, oral	ALECTINIB plasma	Homo sapiens
107 ng/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
85.5 ng/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
306 ng/mL	600 mg 2 times / day steady, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
71.4 ng/mL	600 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
17.5 ng/mL	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
19.3 ng/mL	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
2790 ng × h/mL	600 mg single, oral	ALECTINIB plasma	Homo sapiens
7430 ng × h/mL	600 mg 2 times / day multiple, oral	ALECTINIB unknown	Homo sapiens
1590 ng*h/mL	600 mg single, oral	ALECTINIB plasma	Homo sapiens
7760 ng*h/mL	600 mg 2 times / day steady, oral	ALECTINIB plasma	Homo sapiens
2820 ng*h/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
3710 ng*h/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
2920 ng*h/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
3850 ng*h/mL	300 mg single, oral	ALECTINIB plasma	Homo sapiens
2890 ng*h/mL	600 mg 2 times / day steady, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
471 ng*h/mL	600 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
465 ng*h/mL	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
583 ng*h/mL	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
32 h	600 mg single, oral	ALECTINIB plasma	Homo sapiens
33 h	600 mg 2 times / day multiple, oral	ALECTINIB unknown	Homo sapiens
26.1 h	300 mg single, oral	ALECTINIB plasma	Homo sapiens
39.3 h	300 mg single, oral	ALECTINIB plasma	Homo sapiens
30.5 h	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens
24.5 h	300 mg single, oral	ALECTINIB METABOLITE M4 plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	600 mg 2 times / day multiple, oral		ALECTINIB unknown	Homo sapiens

Doses

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Dose	Population	Adverse events
600 mg 2 times / day steady, oral Recommended	unhealthy, 53 years n = 253	Other AEs: Cough...
900 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 56 years (range: 40–83 years) n = 6	DLT: Neutropenia...
900 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 56 years (range: 40–83 years) n = 6	DLT: Headache...
600 mg 2 times / day steady, oral Recommended	unhealthy, 56 years n = 134	Other AEs: Hyperglycemia, Hyperglycemia...
600 mg 2 times / day steady, oral Recommended	unhealthy, 56 years n = 143	Other AEs: CPK increased, CPK increased...

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AEs

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AE	Significance	Dose	Population
Cough	all grades, 19%	600 mg 2 times / day steady, oral Recommended	unhealthy, 53 years n = 253
Neutropenia	grade 3 DLT, Disc. AE	900 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 56 years (range: 40–83 years) n = 6
Headache	grade 3 DLT, Disc. AE	900 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 56 years (range: 40–83 years) n = 6
Hyperglycemia	all grades, 22%	600 mg 2 times / day steady, oral Recommended	unhealthy, 56 years n = 134
Hyperglycemia	grade 3-4, 2.2%	600 mg 2 times / day steady, oral Recommended	unhealthy, 56 years n = 134

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1,478 CYP2C8 911 BCRP 699 P-gp 1,461 BSEP 402 Cav1.2 45 CYP1A2 1,524 CYP2B6 810 MRP2 383 OATP1B1 788 OAT1 599 OAT2 145 OCT2 647	OATP1B1 406 OATP1B3 350 BCRP 561 P-gp 1,537	CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
BCRP 773	inhibitor 3,277	yes [IC50 0.1 uM]
BSEP 403	inhibitor 3,277	yes [IC50 0.9 uM]
P-gp 1,650	inhibitor 3,277	yes [IC50 1.1 uM]
CYP1A2 1,692	inhibitor 3,277	yes [IC50 >10 uM]
CYP2B6 1,001	inhibitor 3,277	yes [IC50 >10 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
BCRP 561	substrate 3,367	no
OATP1B1 406	substrate 3,367	no
OATP1B3 350	substrate 3,367	no
P-gp 1,537	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 49	inhibitor 1,626
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90936	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90936
ChemicalBook	CB62534680	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62534680
MolPort	MolPort-023-293-545	https://www.molport.com/shop/molecule-link/MolPort-023-293-545
Selleck Chemicals	ch5424802	http://www.selleckchem.com/products/ch5424802.html
ZINC	ZINC000066166864	http://zinc15.docking.org/substances/ZINC000066166864

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PubMed

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Title	Date	PubMed
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.	2007 Aug 2	17625570
KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer.	2009 May 1	19383809
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.	2011 May 17	21575866

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Patents

Sample Use Guides

In Vivo Use Guide

600 mg orally twice daily. Administer with food.

Route of Administration: Oral

In Vitro Use Guide

Alectinib exhibited antiproliferative activity against SNU-2535 cells in vitro with IC50 of 33.1 nM.

Substance Class	Chemical
Record UNII	LIJ4CT1Z3Y
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

ALECTINIB

Official Name

English

ALECTINIB [MI]

Common Name

English

alectinib [INN]

Common Name

English

AF-802

Code

English

RO-5424802

Code

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

462814

Protein kinase inhibitors

WHO-ATC

L01XE36

Established Pharmacologic Class

NDF-RT

N0000175605

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Tyrosine Kinase Inhibitor

NCI_THESAURUS

C141136

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Code System

Code

Type

Description

EVMPD

SUB178557

PRIMARY

LACTMED

Alectinib

PRIMARY

IUPHAR

7739

PRIMARY

PUBCHEM

49806720

PRIMARY

RXCUI

1727455

PRIMARY

RxNorm

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Related Record

Type

Details


					Y6HQW2M2JG

PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET

TARGET -> INHIBITOR

Qualification:

IC50

Amount:

5 NANOMOLAR (average)


					0UY97CSG1T

CYTOCHROME P450 2B6

METABOLIC ENZYME -> SUBSTRATE


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

99 % (average)


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR

Qualification:

IC50

Amount:

1.1 MICROMOLAR (average)


					L0423Z5LDW

CYTOCHROME P450 2C8

METABOLIC ENZYME -> SUBSTRATE

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Related Record

Type

Details


					6L7WLR552I

5H-BENZO(B)CARBAZOLE-3-CARBONITRILE, 9-ETHYL-6,11-DIHYDRO-8-(4-((2-HYDROXYETHYL)AMINO)-1-PIPERIDINYL)-6,6-DIMETHYL-11-OXO-

METABOLITE ACTIVE -> PARENT

Interaction Type:

MAJOR

Qualification:

PLASMA


					83XL789LVX

2-((1-(3-CYANO-9-ETHYL-6,6-DIMETHYL-11-OXO-5H-BENZO(B)CARBAZOL-8-YL)-4-PIPERIDYL)-(2-HYDROXYETHYL)AMINO)ACETIC ACID

METABOLITE -> PARENT


					CX3VX49ATK

8-(4-AMINO-1-PIPERIDINYL)-9-ETHYL-6,11-DIHYDRO-6,6-DIMETHYL-11-OXO-5H-BENZO(B)CARBAZOLE-3-CARBONITRILE

METABOLITE -> PARENT


					P6KVL3K68W

8-(4-(2-ACETONYLOXYETHYLAMINO)-1-PIPERIDYL)-9-ETHYL-6,6-DIMETHYL-11-OXO-5H-BENZO(B)CARBAZOLE-3-CARBONITRILE

METABOLITE -> PARENT

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Related Record

Type

Details


					LIJ4CT1Z3Y

ALECTINIB

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	33 hours (average)

Volume of Distribution	PHARMACOKINETIC	57.4 Liters/Kilogram (average)

Tmax	PHARMACOKINETIC	4 hours (average)	FED CONDITION SINGLE DOSE [460 to 900] mg (average)

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

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator