US 2019/0376971 A1Published application

Compositions and Methods for the Assessment of Drug Target Occupancy for Bruton's Tyrosine Kinase

AssigneeAcerta Pharma B.V.

InventorsTjeerd Barf, Allard Kaptein, Saskia Verkaik, Dennis Demont, Todd Covey, Bas Van De Kar, Bart Van Lith, Michael Gulrajani

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Abstract

In some embodiments, the invention relates to compositions, methods, and kits for assessment of drug target occupancy in Bruton's tyrosine kinase (BTK) in a selective and sensitive manner for use with BTK inhibitor therapy in the treatment of Bruton's tyrosine kinase (BTK) mediated disorders, including cancers, inflammatory diseases, and immune and autoimmune diseases.

Claims23

Dependent claims

A method for determining a drug target occupancy of Bruton's tyrosine kinase (BTK) in a patient after treatment of the patient with a BTK inhibitor, comprising the steps of:

(a) obtaining a tissue sample from the patient;
(b) separating a population of cells from the tissue sample;
(c) contacting a BTK probe with the population of cells;
(d) detecting the amount of BTK bound to the BTK probe using an assay;
(e) determining the drug target occupancy of BTK in the population of cells based on the amount of BTK bound to the BTK probe;
and
(f) optionally performing a second assay for PLCγ2 phosphorylation;
wherein the BTK probe is a compound according to:
or a salt or complex thereof, wherein:
X is CH or S;
Y is C(R6);
Z is CH or bond;
A is CH;
B1 is N or C(R7);
B2 is N or C(R8);
B3 is N or CH;
B4 is N or CH;
R1 is C(═O)R11,
R2 is (C1-3)alkyl;
R3 is (C1-3)alkyl;
R2 and R3 form a (C3-7)heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, optionally substituted with one or more fluorine, hydroxyl, (C1-3)alkyl, or (C1-3)alkoxy;
R4 is H;
R5 is H, halogen, cyano, (C1-4)alkyl, (C1-3)alkoxy, (C3-6)cycloalkyl, or any alkyl group of which is optionally substituted with one or more halogen;
R6 is H or (C1-3)alkyl;
R7 is H, halogen or (C1-3)alkoxy;
R8 is H or (C1-3)alkyl;
or
R7 and R8 form, together with the carbon atom they are attached to a (C6-10)aryl or (C1-9)heteroaryl;
R5 and R6 together may form a (C3-7)cycloalkenyl or (C2-6)heterocycloalkenyl, each optionally substituted with (C1-3)alkyl or one or more halogen;
with the proviso that 0 to 2 atoms of B1, B2, B3, and B4 are N;
R11 is selected from the group consisting of (C2-6)alkenyl-R12 and (C2-6)alkynyl-R12;
and
R12 is L1-L2-(L3)m-(L4-)n-W, wherein:
L1 is selected from the group consisting of heterocycloalkyl and heteroalkyl;
L2 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
L3 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
L4 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
m is 0 to 5;
n is 0 to 5;
and
W is:

38 more elements

A kit for determining drug target occupancy in a patient receiving BTK inhibitor therapy, comprising a BTK probe according to:

or a salt or complex thereof, wherein:
X is CH or S;
Y is C(R8);
Z is CH or bond;
A is CH;
B1 is N or C(R7);
B2 is N or C(R8);
B3 is N or CH;
B4 is N or CH;
R1 is C(═O)R11,
R2 is (C1-3)alkyl;
R3 is (C1-3)alkyl;
R2 and R3 form a (C3-7)heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, optionally substituted with one or more fluorine, hydroxyl, (C1-3)alkyl, or (C1-3)alkoxy;
R4 is H;
R5 is H, halogen, cyano, (C1-4)alkyl, (C1-3)alkoxy, (C3-6)cycloalkyl, or any alkyl group of which is optionally substituted with one or more halogen;
R6 is H or (C1-3)alkyl;
R7 is H, halogen or (C1-3)alkoxy;
R8 is H or (C1-3)alkyl;
or
R7 and R8 form, together with the carbon atom they are attached to a (C6-10)aryl or (C1-9)heteroaryl;
R5 and R6 together may form a (C3-7)cycloalkenyl or (C2-6)heterocycloalkenyl, each optionally substituted with (C1-3)alkyl or one or more halogen;
with the proviso that 0 to 2 atoms of B1, B2, B3, and B4 are N;
R11 is selected from the group consisting of (C2-6)alkenyl-R12 and (C2-6)alkynyl-R12;
and
R12 is L1-L2-(L3)m-(L4-)n-W, wherein:
L1 is selected from the group consisting of heterocycloalkyl and heteroalkyl;
L2 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
L3 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
L4 is a linear linker group selected from the group consisting of (C1-5)alkylamide, (C1-5)alkoxy, and a bond;
m is 0 to 5;
n is 0 to 5;
and
W is:

30 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/477,395Filed 19 Jan 2018
Priority: 19 Jan 2017
Published: 12 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

G01N 33/573
Immunoassay; Biospecific binding assay; Materials therefor: for enzymes or isoenzymes
C07D 495/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
C12Q 1/485
Involving transferase: involving kinase

Family

Application62/448,077Us provisional application · filed 19 Jan 2017
US 2019/0376971 A1This patent

From the US filing history. Foreign family members aren’t listed.

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