Tirbanibulin

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H29N3O3
Molecular Weight	431.5268
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

O=C(CC1=NC=C(C=C1)C2=CC=C(OCCN3CCOCC3)C=C2)NCC4=CC=CC=C4

InChI

InChIKey=HUNGUWOZPQBXGX-UHFFFAOYSA-N

InChI=1S/C26H29N3O3/c30-26(28-19-21-4-2-1-3-5-21)18-24-9-6-23(20-27-24)22-7-10-25(11-8-22)32-17-14-29-12-15-31-16-13-29/h1-11,20H,12-19H2,(H,28,30)

HIDE SMILES / InChI

Molecular Formula	C26H29N3O3
Molecular Weight	431.5268
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

KX-01 is a dual inhibitor of Src kinase and tubulin polymerization. KX01 promotes the induction of p53, G2/M arrest of proliferating cell populations and subsequent apoptosis via the stimulation of Caspase-3 and PARP cleavage. The drug was developed by Kinex Pharmaceuticals and reached phase II of clinical trials for the treatment of Castration-Resistant Prostate Cancer and Actinic Keratosis. KX-01 demonstrated good in vitro pofile against different cancer cell lines with IC50 in nanomolar range.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase SRC 19	Inhibitor 8,504
tubulin complex assembly 1	Inhibitor 8,504

Conditions

Condition	Modality	Targets	Highest Phase	Product
Castrate-resistant prostate cancer 20	Primary		Phase II 1,147	Unknown
Actinic keratosis 12	Primary		Phase II 1,147	Unknown

C_max

Value	Dose	Analyte	Population
0.34 ng/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
0.18 ng/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
0.26 ng/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
3.61 ng/mL	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.73 ng/mL	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
9.55 ng/mL	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
16.6 ng/mL	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
26.45 ng/mL	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
14.9 ng/mL	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
37.85 ng/mL	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
33.85 ng/mL	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
79.75 ng/mL	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
73.1 ng/mL	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
58.7 ng/mL	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
60.5 ng/mL	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
188 ng/mL	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
21.7 ng/mL	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
117 ng/mL	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
98.6 ng/mL	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
273 ng/mL	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
143.3 ng/mL	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
5 ng × h/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
3.18 ng × h/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
4.09 ng × h/mL	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
15.39 ng × h/mL	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
16.28 ng × h/mL	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
31 ng × h/mL	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
85.95 ng × h/mL	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
68.65 ng × h/mL	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
58.48 ng × h/mL	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
143.79 ng × h/mL	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
104.49 ng × h/mL	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
332.97 ng × h/mL	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
336.09 ng × h/mL	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
196.78 ng × h/mL	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
166.75 ng × h/mL	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
1898.74 ng × h/mL	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
94.2 ng × h/mL	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
360.42 ng × h/mL	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
298.27 ng × h/mL	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
984.8 ng × h/mL	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
560.25 ng × h/mL	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
1 day	250 mg 1 times / day multiple, topical	KX-01 plasma	Homo sapiens
3.95 h	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.45 h	2 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.01 h	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
4.95 h	5 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
2.98 h	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
2.96 h	10 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
5.6 h	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.52 h	20 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.47 h	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
4.53 h	40 mg 2 times / day multiple, oral	KX-01 plasma	Homo sapiens
3.4 h	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
4.63 h	40 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
9.34 h	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
3.22 h	50 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
3.77 h	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
4.67 h	60 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
2.89 h	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens
5.7 h	80 mg 2 times / day steady-state, oral	KX-01 plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
17%			KX-01 serum	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
80 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT	DLT: Neutropenia, AST increased...
40 mg 2 times / day multiple, oral MTD	unhealthy, ADULT
1 % 1 times / day multiple, topical Recommended	unhealthy, ADULT
50 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT	DLT: AST increased, Thrombocytopenia...
60 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT	DLT: AST increased, ALT increased...

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AEs

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AE	Significance	Dose	Population
AST increased	grade 3, 33.3% DLT, Disc. AE	80 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT
Neutropenia	grade 4, 33.3% DLT, Disc. AE	80 mg 2 times / day multiple, oral Highest studied dose	unhealthy, ADULT
AST increased	grade 3, 25% DLT, Disc. AE	50 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT
Thrombocytopenia	grade 3, 25% DLT, Disc. AE	50 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT
ALT increased	grade 3, 16.7% DLT, Disc. AE	60 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT

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PubMed

Show entries

Title	Date	PubMed
Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors.	2011 Apr 15	21459579
Thiazolyl N-benzyl-substituted acetamide derivatives: synthesis, Src kinase inhibitory and anticancer activities.	2011 Oct	21852023
KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer.	2012 Apr	21509526
A phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies.	2013 Aug	23361621

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Patents

Sample Use Guides

In Vivo Use Guide

Patients recieve 40 mg of oral KX-01 twice-daily. Ointment form should be applied once daily.

Route of Administration: Other

In Vitro Use Guide

PC3-LN4 human prostate cancer cells were treated with 10(-4)-10(4) nM of KX-01 for 72 hours and GI50 value was determined to be 40 nM.

Substance Class	Chemical
Record UNII	4V9848RS5G
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

Tirbanibulin

Official Name

English

KX-01

Preferred Name

English

KX2391

Code

English

KX-2-391

Code

English

KLISYRI

Brand Name

English

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Code System

Code

Type

Description

FDA UNII

4V9848RS5G

PRIMARY

USAN

GH-126

PRIMARY

ChEMBL

CHEMBL571546

PRIMARY

DRUG BANK

DB06137

PRIMARY

DAILYMED

4V9848RS5G

PRIMARY

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Related Record

Type

Details


					6NP3XSMIP3

MULTIDRUG AND TOXIN EXTRUSION PROTEIN 1

TRANSPORTER -> INHIBITOR

Comments:

The results suggest that KLISYRI has no clinically meaningful effect on the PK of drugs mediated by MATE1

Qualification:

IC50

Amount:

[>1] MICROMOLAR (average)


					66DDF797LP

OATP-8

TRANSPORTER -> INHIBITOR

Comments:

The results suggest that KLISYRI has no clinically meaningful effect on the PK of drugs mediated by OATP1B3

Qualification:

IC50

Amount:

[>1] MICROMOLAR (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Comments:

Plasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 ?g/mL.

Interaction Type:

BINDING

Amount:

88 % (average)


					L0423Z5LDW

CYTOCHROME P450 2C8

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MINOR


					4V0HB10Q7P

TUBULIN ALPHA-1A CHAIN

TARGET->INHIBITOR OF AGGREGATION

Amount:

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Related Record

Type

Details


					4V9848RS5G

Tirbanibulin

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Referenced Substance	Defining	Parameters	References
Tmax	PHARMACOKINETIC	7 hours (average)

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound