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Potent and Specific Jak2 Inhibitors for the Treatment of Blood Cancers

标题

Identification of a Diverse Portfolio of Jak2 Small Molecule Inhibitors

详细技术说明

None

*Abstract

Introduction

These potent and specific inhibitors facilitate the study and treatment of leukemia, lymphoma, and other blood cancers, as well as cardiovascular and ophthalmic diseases. Scientists often rely on inhibitors to study the relationship between the enzyme Jak2 and a variety of diseases, including cancer, diabetes, and hypertension. A pharmacological Jak2 inhibitor commonly used in research is AG490. While AG490 inhibits Jak2, it also inhibits other tyrosine kinases, making Jak2 studies difficult. AG490’s broad inhibitory action presents a challenge for using AG490 as a therapeutic agent.

Researchers at the University of Florida have identified compounds that function as effective and specific Jak2 inhibitors. These compounds will allow researchers specifically to inhibit Jak2, which in turn may provide a better understanding of how Jak2 correlates with these diseases and provide for a new class of drugs for those suffering from Jak2 related disorders.

Application

Effective and specific inhibitors of Jak2 for the study and treatment of various diseases including Myeloproliferative Disorders (MPDs), such as leukemia, lymphoma, and other blood cancers, as well as cardiovascular and ophthalmic diseases

Advantages

• Provides the basis for a novel class of drugs for Myeloproliferative Disorders, offering broad market applications
• Compounds are specific to Jak2 and discriminate between Jak2 and other similar kinases, enabling beneficial outcomes associated with inhibition of Jak2 while avoiding the negative impact of inhibiting other kinases

Technology

Jak2 plays an important role in cell development and growth by activating and deactivating other proteins. Jak2 functions as a non-receptor member of the Janus kinase (Jak) family of tyrosine kinases. It has been implicated in certain types of cancer, diabetes and Myeloproliferative Disorders (MPDs). Once activated, Jak2 phosphorylates its substrate proteins, which in turn induce gene transcription. These compounds developed at the University of Florida inhibit phosphorylation of Jak2 in both a time and dose-dependent fashion, including the disease associated Jak2-V617F mutant. Unlike currently available Jak2 pharmacological inhibitors such as AG490, these compounds potently and specifically inhibit Jak2, providing a therapeutic alternative for patients suffering from MPDs and other Jak2 related diseases.

*IP Issue Date

Feb 5, 2013

*IP Publication Date

Nov 4, 2010

*Principal Investigation

Name: Peter Sayeski

Department:

Name: Gyorgy Keseru

Department:

附加资料

Patent Number: US8367078B2
Application Number: US2010663521A
Inventor: Sayeski, Peter P. | Keserü, György M.
Priority Date: 6 Jun 2007
Priority Number: US8367078B2
Application Date: 12 Jul 2010
Publication Date: 5 Feb 2013
IPC Current: A61K000900 | A01N005926 | A61K000920 | A61K000948 | A61K003342 | A61K004700 | C07C004920 | C07C025500 | C07F000922 | G01N003320
US Class: 424400 | 424439 | 424451 | 424463 | 424464 | 424489 | 424601 | 436081 | 558303 | 558385 | 562008 | 562011 | 568008 | 568303 | 568307 | 568382 | 568414 | 568415 | 568700 | 568702
Assignee Applicant: University of Florida Research Foundation Inc.inesville
Title: Kinase inhibitor compounds
Usefulness: Kinase inhibitor compounds
Summary: (I) is useful for treating JAK2 mediated disorder and for reducing Jak2-dependent cell growth in a subject, preferably human, where: the JAK2 mediated disorder is hematological disease or disorder (including polycythemia vera, essential thrombocythemia, angiogenic myeloid metaplasia, and primary myelofibrosis), cancer (including leukemias (which is chronic myelogenous leukemia, acute myeloid leukemia and acute promyelocytic leukemia), lymphomas, myelomas and solid tumors), and a cardiac disease or disorder (including cardiac hypertrophy, cardiac ischemia-reperfusion and heart failure); the subject is identified as having the Jak2-V617F mutant, or K603Q, D620E or C644S mutation in the Jak2 JH2 domain; or the subject is identified as having the K603Q, D620E and C644S mutations in the Jak2 JH2 domain and is identified as not having the Jak2-V617F mutant (all claimed); and the cancer is e.g. chronic leukemia, polycythemia vera, Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, nile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. The ability of 2-(diethylaminomethyl)-4-[4-[3-(diethylaminomethyl)-4-hydroxy-phenyl]hex-3-en-3-yl]phenol (G6) to treat Jak2-V617F-induced hematopoetic disease was tested in severe combined immunodeficient (SCID) mouse model. The result showed that (G6) reduced human erythroleukemic cell induced increase in the percent of circulating blast cells by 50 percent.
Novelty: Treating janus kinases-2 mediated disorder e.g. cancer, comprises administering e.g. (diethylaminomethyl)-4-(4-((diethylaminomethyl)-hydroxy-phenyl)hexenyl)phenol, dibutoxyphosphoryloxypentanenitrile or ytterbium trihydroxide

主要类别

诊断/治疗

细分类别

癌症/肿瘤

申请日期

Jul 12, 2010

申请号码

8,367,078

其他

国家/地区

美国