Kinase mutants and uses thereof

Patent metadata

Field	Value
Publication number	US-11738049-B2
Application number	US-201816615032-A
Country	US
Kind code	B2
Filing date	May 24, 2018
Priority date	May 24, 2017
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The present invention relates to methods of designing kinase mutants for reprogramming the sensitivity of a target kinase to some specific inhibitors, methods of reprogramming the sensitivity of a target kinase to some specific inhibitors, wherein those kinase inhibitors have little or no affinity for the wild-type target kinase, vectors or cells expressing said mutated kinases, composition and uses thereof for the prevention and/or treatment of a disease or disorder, in particular cancer.

First claim

The invention claimed is:

1. A Zap-70 kinase mutant that retains functional activity of wild-type Zap-70 kinase and is more sensitive than wild-type Zap-70 kinase to inhibition by erlotinib and vandetanib, wherein said Zap-70 kinase mutant comprises an amino acid sequence of SEQ ID NO: 1 wherein is introduced at least one mutation selected from: V399I, M414A, M414T, M414V, M416Y, M416V, M416L, M4161, M416F, M416W, M416H, M416T and M416S.

2. The A Zap-70 kinase mutant that retains functional activity of wild-type Zap-70 kinase and is more sensitive than wild-type Zap-70 kinase to inhibition by erlotinib and vandetanib, wherein said Zap-70 kinase mutant comprises an amino acid sequence selected from SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.

3. The Zap-70 kinase mutant according to claim 1 , said mutant comprising an amino acid sequence selected from SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.

4. The Zap-70 kinase mutant according to claim 1 comprising an amino acid sequence of SEQ ID NO: 1 wherein is introduced the mutation M414A, and at least one conservative substitution of at least one amino acid on at least one position selected from 342, 344-346, 350-354, 367-369, 386, 390, 399, 412, 413, 415-421, 424, 466-468 and 478-480.

5. A kit comprising at least one kinase mutant according to claim 1 and instructional material.

6. The Zap-70 kinase mutant of claim 1 further comprising at least one conservative substitution of at least one amino acid of the mutated SEQ ID NO: 1 on at least one position selected from 342, 344-346, 350-354, 367-369, 386, 390, 399, 412-421, 424, 466-468 and 478-480 which was not mutated.

Assignees

• Sib Swiss Inst Of Bioinformatics
• Chuv—Centre Hospitalier Univ Vaudois
• Univ Lausanne
• Ludwig Inst For Cancer Res Ltd

Inventors

• Michielin Olivier
• Zoete Vincent
• Coukos George
• Irving Melita
• Dilek Nahzli
• Reichenbach Patrick
• Ascencao Kelly

Classifications

• A61K35/17 Primary

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• A61K31/517 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07K14/55

  IL-2 · CPC title

• C12N9/1205

  Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases · CPC title

• C12N15/1024

  In vivo mutagenesis using high mutation rate "mutator" host strains by inserting genetic material, e.g. encoding an error prone polymerase, disrupting a gene for mismatch repair · CPC title