OLMUTINIB

Possibly Marketed Outside US

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H26N6O2S
Molecular Weight	486.589
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN1CCN(CC1)C2=CC=C(NC3=NC(OC4=CC=CC(NC(=O)C=C)=C4)=C5SC=CC5=N3)C=C2

InChI

InChIKey=FDMQDKQUTRLUBU-UHFFFAOYSA-N

InChI=1S/C26H26N6O2S/c1-3-23(33)27-19-5-4-6-21(17-19)34-25-24-22(11-16-35-24)29-26(30-25)28-18-7-9-20(10-8-18)32-14-12-31(2)13-15-32/h3-11,16-17H,1,12-15H2,2H3,(H,27,33)(H,28,29,30)

HIDE SMILES / InChI

Molecular Formula	C26H26N6O2S
Molecular Weight	486.589
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

Olmutinib is a novel third-generation epidermal growth factor receptor (EGFR) mutation-specific tyrosine kinase inhibitor, used in the treatment of T790M mutation positive non-small cell lung cancer. Olmutinib covalently binds a cysteine residue near the kinase domain of mutant EGFRs to prevent phosphorylation of the receptor. EGFRs are frequently over-expressed in lung cancer and contribute to activation of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways which both promote cell survival and proliferation. By inhibiting EGFR activation, Olmutinib attenuates the activation of these tumor-promoting pathways. In the first phase I/II clinical study of Osimertinib, 800 mg/ day was chosen as the dose for subsequent studies, and the dose-limiting toxicity and maximum tolerated dose was not reached. Olmutinib received breakthrough therapy designation in the United States in December 2015 and was approved for use in Korea in May 2016.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Epidermal growth factor receptor	Inhibitor		10.0 nM [IC50]
Tyrosine-protein kinase BTK	Inhibitor		1.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer	Primary		Phase II	Unknown

C_max

Value	Dose	Analyte	Population
441.4 ng/mL	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
931 ng/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
1089.2 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
1322.7 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
910.8 ng/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
1396.7 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
982.1 ng/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
1495.7 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
941.3 ng/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
1327.2 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
267 ng/mL	50 mg single, oral	OLMUTINIB plasma	Homo sapiens
845 ng/mL	75 mg single, oral	OLMUTINIB plasma	Homo sapiens
932 ng/mL	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
1226 ng/mL	150 mg single, oral	OLMUTINIB plasma	Homo sapiens
2565 ng/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
2043 ng/mL	250 mg single, oral	OLMUTINIB plasma	Homo sapiens
2432 ng/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3889.1 ng × h/mL	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
9383.2 ng × h/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
10792.7 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
12766.4 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
8452.8 ng × h/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
13024.3 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
7483.4 ng × h/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
13882.2 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
8439.8 ng × h/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
12566.4 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
3574 ng × h/mL	50 mg single, oral	OLMUTINIB plasma	Homo sapiens
9105 ng × h/mL	75 mg single, oral	OLMUTINIB plasma	Homo sapiens
12322 ng × h/mL	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
15537 ng × h/mL	150 mg single, oral	OLMUTINIB plasma	Homo sapiens
36618 ng × h/mL	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
28339 ng × h/mL	250 mg single, oral	OLMUTINIB plasma	Homo sapiens
42198 ng × h/mL	300 mg single, oral	OLMUTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
5 h	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
7.4 h	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
5.7 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
5.7 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
6 h	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
6.1 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
4.8 h	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
5.6 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
6 h	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
5.8 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens
11.3 h	50 mg single, oral	OLMUTINIB plasma	Homo sapiens
8.2 h	75 mg single, oral	OLMUTINIB plasma	Homo sapiens
9 h	100 mg single, oral	OLMUTINIB plasma	Homo sapiens
8.6 h	150 mg single, oral	OLMUTINIB plasma	Homo sapiens
9.4 h	200 mg single, oral	OLMUTINIB plasma	Homo sapiens
8.6 h	250 mg single, oral	OLMUTINIB plasma	Homo sapiens
11.3 h	300 mg single, oral	OLMUTINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.2%	unknown, dental		OLMUTINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
1200 mg 1 times / day multiple, oral Highest studied dose	unhealthy, ADULT	DLT: abdominal pain, diarrhea...
800 mg 1 times / day multiple, oral MTD	unhealthy, ADULT	Other AEs: Diarrhea, Diarrhea...
800 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT	Disc. AE: epidermal necrolysis... Other AEs: Diarrhea, Diarrhea...

Showing 1 to 3 of 3 entries

Previous1Next

AEs

Show entries

AE	Significance	Dose	Population
abdominal pain	grade 3, 2 patients DLT	1200 mg 1 times / day multiple, oral Highest studied dose	unhealthy, ADULT
diarrhea	grade 3, 2 patients DLT	1200 mg 1 times / day multiple, oral Highest studied dose	unhealthy, ADULT
Diarrhea	all grades, 101 patient	800 mg 1 times / day multiple, oral MTD	unhealthy, ADULT
Pyrexia	all grades, 16 patients	800 mg 1 times / day multiple, oral MTD	unhealthy, ADULT
Nail disorder	all grades, 17 patients	800 mg 1 times / day multiple, oral MTD	unhealthy, ADULT

Showing 1 to 5 of 57 entries

Previous1 2 3 4 5…12Next

PubMed

Show entries

Title	Date	PubMed
Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton's tyrosine kinase inhibitors.	2016 Jul 1	27210433

Showing 1 to 1 of 1 entries

Previous1Next

Patents

Sample Use Guides

In Vivo Use Guide

800 mg QD (2 x 400 mg tablets) continuously in 21-day cycles

Route of Administration: Oral

In Vitro Use Guide

Olmutinib was evaluated with the BTK kinase inhibition using Z'-LYTE™ fluorescence resonance energy transfer (FRET) method and ibrutinib was used as the reference compounds. The Z'-LYTE™ biochemical assay employs a FRET-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with two fluorophores-one at each end-that make up a FRET pair. In the primary reaction (the Kinase Reaction), the kinase transfers the g-phosphate of ATP to a single serine or threonine residue in the synthetic peptide substrate. In the secondary reaction (the Development Reaction), a site-specific protease (the Development Reagent) recognizes and cleaves nonphosphorylated peptides. Phosphorylated peptides exhibit suppressed cleavage by the Development Reagent. Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophores on the peptide, whereas uncleaved, phosphorylated peptides maintain FRET. A ratiometric method, which calculates the ratio (the Emission Ratio) of donor emission to acceptor emission after excitation of the donor fluorophore at 400 nm