KR20220162641A - JAK PROTAC chimeric molecule and Pharmaceutical composition for treatment of disease involving JAK peptide - Google Patents
JAK PROTAC chimeric molecule and Pharmaceutical composition for treatment of disease involving JAK peptide Download PDFInfo
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- KR20220162641A KR20220162641A KR1020220066790A KR20220066790A KR20220162641A KR 20220162641 A KR20220162641 A KR 20220162641A KR 1020220066790 A KR1020220066790 A KR 1020220066790A KR 20220066790 A KR20220066790 A KR 20220066790A KR 20220162641 A KR20220162641 A KR 20220162641A
- Authority
- KR
- South Korea
- Prior art keywords
- protein
- jakpp
- jak
- binding domain
- peptide
- Prior art date
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- 108010009962 valyltyrosine Proteins 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
Abstract
Description
본 발명은 신규 JAK 프로탁 유도체, 이의 제조방법과 이를 포함하는 JAK관련 질환의 치료 또는 예방용 약물학적 조성물에 관한 것으로, 본 발명의 일측면에서 제공되는 신규 JAK 프로탁 유도체는 유비퀴틴 프로테오좀 단백질 분해 시스템 조절자 E3 리가아제와 결합하여 세포내 JAK 단백질 분해에 우수한 효과를 나타내므로 천식 또는 아토피 등의 알러지성 질환 및 암의 예방/치료용 약학 조성물로 유용하게 사용될 수 있다.The present invention relates to a novel JAK protac derivative, a method for preparing the same, and a pharmacological composition for treating or preventing JAK-related diseases including the same. Since it binds to the degradation system regulator E3 ligase and exhibits excellent effects on intracellular JAK protein degradation, it can be usefully used as a pharmaceutical composition for preventing/treating allergic diseases such as asthma or atopy and cancer.
프로탁(PROTAC)은 단백질 가수분해 표적화 키메라(proteolysis targeting chimera)의 약자로 세포내 단백질가수분해를 유도하여 원치 않은 단백질을 선택적으로 제거할 수 있도록 한다. 프로탁은 표적 단백질의 리간드와 E3 리가아제에 결합하는 리간드가 링커를 통해 연결된 이종이량체 분자이다. 프로탁은 양쪽 단백질에 동시에 결합하여 표적단백질을 E3 리가아제에 매우 근접하게 접근하도록 해주며, 이를 통해 E3 리가아제는 표적단백질을 기질로 인식하여 폴리유비퀴틴화 및 후속 프로테아좀 분해를 유발한다. N-데그론 경로는 기질 단백질의 N-말단의 아미노산들을 인식하여 단백질을 분해하는 시스템이으로 기질 단백질의 N-말단 아미노산들이 UBR E3 유비퀴틴 리가아제 패밀리에 의해 인식되어 기질 단백질의 유비퀴틴화 및 프로테아좀에 의한 분해 과정을 거치게 된다. 프로탁은 이러한 원리를 이용하여 물리적으로 서로 다른 곳에 있던 단백질을 가까이 위치하도록 만들고 특정 단백질을 세포 내에서 효과적으로 제거할 수 있다. 기존 약물들은 표적 단백질의 기능을 억제할 수 있는 특정 활성 부위나 결합 부위에 반드시 결합해야만 약효를 낼 수 있는 반면, 프로탁은 결합 부위와 상관없이 표적 단백질을 분해할 수 있는 위치에 가깝게 붙들어 둘 수만 있으면 표적 단백질을 분해하여 기능을 억제할 수 있는 장점이 있다. 이러한 점에서, 프로탁은 질병의 치료제로서의 높은 잠재성을 지니고 있다.PROTAC is an abbreviation of proteolysis targeting chimera, which induces intracellular proteolysis to selectively remove unwanted proteins. Protac is a heterodimeric molecule in which a ligand of a target protein and a ligand binding to E3 ligase are connected through a linker. Protac binds to both proteins simultaneously, bringing the target protein into close proximity to the E3 ligase, which recognizes the target protein as a substrate and triggers polyubiquitination and subsequent proteasomal degradation. The N-degron pathway is a system that degrades proteins by recognizing N-terminal amino acids of substrate proteins. The N-terminal amino acids of substrate proteins are recognized by the UBR E3 ubiquitin ligase family to ubiquitinate and protease substrate proteins. It goes through the process of decomposition by moths. Protac uses this principle to bring proteins that were physically different from each other closer together and can effectively remove specific proteins from cells. Whereas existing drugs must bind to a specific active site or binding site that can inhibit the function of a target protein, Protac can only bind to a target protein close to a position where it can be degraded, regardless of the binding site. If present, it has the advantage of inhibiting the function by degrading the target protein. In this respect, Protac has high potential as a therapeutic agent for diseases.
야누스 키나제(Janus kinase, 이하 'JAK'라 함)는 림프-조혈계에서 세포 기능을 조절하는데 있어 중추적 역할을 하는 세포질 단백질 티로신 키나제이다. JAK는 티로신 인산화 반응을 통해 STAT(Signal Transducer and activators of Transcription, 신호 변환 및 전사인자 활성화) 단백질을 활성화시켜 사이토카인에 신속하게 신호전달경로를 제공한다. JAK/STAT 신호전달이 알러지, 천식, 자가면역질환(예를 들어, 이식거부, 류마티스 관절염, 근위축성 측삭 경화증, 다발성 경화증), 고형암, 혈액암(예를 들어, 백혈병, 림프종 등)에 관련된 것으로 알려져 있다. JAK 단백질 패밀리는 JAK1, JAK2, JAK3, Tyk2 등 4 종류로 구분된다. 현재 여러 제약사들은 JAK 단백질 억제활성이 우수한 신약을 개발하고자 하고 있다. Janus kinase (hereinafter referred to as 'JAK') is a cytoplasmic protein tyrosine kinase that plays a central role in regulating cell functions in the lympho-hematopoietic system. JAK activates STAT (Signal Transducer and Activators of Transcription) protein through tyrosine phosphorylation, and provides a rapid signal transduction pathway to cytokines. JAK/STAT signaling has been implicated in allergy, asthma, autoimmune diseases (e.g. transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis), solid tumors, and hematological cancers (e.g. leukemia, lymphoma, etc.). It is known. The JAK protein family is divided into four types: JAK1, JAK2, JAK3, and Tyk2. Currently, several pharmaceutical companies are trying to develop new drugs with excellent JAK protein inhibitory activity.
본 발명자들은 신규한 JAK 프로탁 유도체가 세포 내 JAK 단백질의 분해에 우수한 효과를 나타내는 것을 확인하고 JAK 관련 질환의 치료 및 예방에 유용하게 사용될 수 있는 본 발명을 완성하게 되었다. The present inventors confirmed that the novel JAK protac derivative exhibits excellent effects on the degradation of intracellular JAK protein and completed the present invention, which can be usefully used for the treatment and prevention of JAK-related diseases.
본 발명이 해결하고자 하는 과제는 JAK단백질 결합 도메인, 유비퀴틴 리가아제 결합 도메인, 및 상기 유비퀴틴 리가아제 결합 도메인과 상기 단백질 결합 도메인에 연결된 링커 도메인을 포함하는 키메라 분자를 제공하는 것이다. An object of the present invention is to provide a chimeric molecule comprising a JAK protein binding domain, a ubiquitin ligase binding domain, and a linker domain linked to the ubiquitin ligase binding domain and the protein binding domain.
또한, 본 발명의 해결 과제는 상기 키메라 분자를 포함하는 JAK 단백질 관련 질환의 치료 또는 예방용 약학 조성물을 제공하는 것이다. In addition, an object of the present invention is to provide a pharmaceutical composition for treating or preventing JAK protein-related diseases, including the chimeric molecule.
또한, 본 발명의 해결 과제는 상기 키메라 분자를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 JAK 단백질 관련 질환의 예방 또는 치료방법을 제공하는 것이다.In addition, an object of the present invention is to provide a method for preventing or treating a JAK protein-related disease, comprising administering the chimeric molecule to a subject in need thereof.
또한, 본 발명의 해결 과제는 JAK 단백질 관련 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한, 상기 키메라 분자의 용도(use)를 제공하는 것이다.In addition, an object to be solved by the present invention is to provide a use of the chimeric molecule for preparing a medicament for use in preventing or treating a JAK protein-related disease.
또한, 본 발명의 해결 과제는 상기 키메라 분자와, 약제학적으로 허용가능한 첨가제를 포함하는 것을 특징으로 하는 약학 조성물을 제공하는 것이다. In addition, an object of the present invention is to provide a pharmaceutical composition comprising the chimeric molecule and a pharmaceutically acceptable additive.
본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 기술적 과제로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.The technical problem to be achieved by the present invention is not limited to the above-mentioned technical problem, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.
상기 과제를 해결하기 위하여, 본 발명은 일 실시예에서 JAK단백질 결합 도메인, 유비퀴틴 리가아제 결합 도메인, 및 상기 유비퀴틴 리가아제 결합 도메인과 상기 단백질 결합 도메인에 연결된 링커 도메인을 포함하는 키메라 분자를 제공한다. In order to solve the above problems, in one embodiment, the present invention provides a chimeric molecule comprising a JAK protein binding domain, a ubiquitin ligase binding domain, and a linker domain linked to the ubiquitin ligase binding domain and the protein binding domain.
본 발명에 있어서, 상기 단백질 결합 도메인은 JAK1 단백질, JAK2 단백질 및 JAK3 단백질로 구성된 군에서 선택되는 어느 하나의 JAK 단백질에 결합하는 것을 특징으로 할 수 있다. In the present invention, the protein binding domain may bind to any one JAK protein selected from the group consisting of JAK1 protein, JAK2 protein and JAK3 protein.
본 발명에 있어서, 상기 단백질 결합 도메인은 서열번호 1 내지 서열번호 18로 구성된 군에서 선택되는 어느 하나의 아미노산 서열을 포함하는 펩타이드인 것을 특징으로 할 수 있다. In the present invention, the protein binding domain may be characterized in that it is a peptide comprising any one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 18.
본 발명에 있어서, 상기 단백질 결합 도메인은 서열번호 1의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK2 단백질인 것을 특징으로 할 수 있다. In the present invention, the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 1, and the JAK protein may be a JAK2 protein.
본 발명에 있어서, 상기 단백질 결합 도메인은 서열번호 8의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK3 단백질인 것을 특징으로 할 수 있다. In the present invention, the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 8, and the JAK protein may be a JAK3 protein.
본 발명에 있어서, 상기 단백질 결합 도메인은 서열번호 14의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK1 단백질인 것을 특징으로 할 수 있다. In the present invention, the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 14, and the JAK protein may be a JAK1 protein.
본 발명에 있어서, 상기 유비퀴틴 리가아제 결합 도메인은 E3 유비퀴틴 리가아제에 결합하는 것을 특징으로 할 수 있고, UBR1(ubiquitin-protein ligase E3 component n-recognin 1) 또는 UBR2(ubiquitin-protein ligase E3 component n-recognin 2)일 수 있다. In the present invention, the ubiquitin ligase binding domain may be characterized by binding to E3 ubiquitin ligase, UBR1 (ubiquitin-protein ligase E3 component n-recognin 1) or UBR2 (ubiquitin-protein ligase E3 component n- recognized 2).
상기 과제를 해결하기 위하여, 본 발명의 다른 실시예는 상기 키메라 분자를 포함하는 JAK 단백질 관련 질환의 치료 또는 예방용 약학 조성물을 제공한다. In order to solve the above problems, another embodiment of the present invention provides a pharmaceutical composition for treating or preventing JAK protein-related diseases including the chimeric molecule.
본 발명에 있어서, 상기 약학 조성물은 천식, 알레르기성 피부염, 아토피성 피부염, 건선 및 암으로 구성된 군에서 선택되는 질환의 치료 또는 예방용 약학 조성물일 수 있다. In the present invention, the pharmaceutical composition may be a pharmaceutical composition for treatment or prevention of a disease selected from the group consisting of asthma, allergic dermatitis, atopic dermatitis, psoriasis and cancer.
본 발명의 다른 실시예는 상기 키메라 분자와, 약제학적으로 허용가능한 첨가제를 포함하는 것을 특징으로 하는 약학 조성물을 제공한다. Another embodiment of the present invention provides a pharmaceutical composition comprising the chimeric molecule and a pharmaceutically acceptable additive.
본 발명에 따른 신규 JAK 프로탁 유도체는 유비퀴틴 프로테오좀 단백질 분해 시스템 조절자 E3리가아제와 결합하여 세포 내 JAK 단백질의 분해에 우수한 효과를 나타내고, 천식, 아토피 등 알러지성 질환 및 암의 예방/치료에 효과적이다. The novel JAK protac derivative according to the present invention binds to the ubiquitin proteosome proteolysis system regulator E3 ligase, exhibits excellent effects in degrading JAK protein in cells, and prevents/treats allergic diseases such as asthma and atopy and cancer. effective for
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the description of the present invention or the configuration of the invention described in the claims.
도 1은 HEK293T 세포에서 JAK 프로탁 유도체와 UBR1 및 UBR2의 결합을 확인한 결과이다.
도 2 내지 도 6은 비만세포주 HMC 1.1에서 JAK 프로탁 유도체의 활성 평가 결과를 나타낸 것이다. 1 shows the results of confirming the binding between JAK protac derivatives and UBR1 and UBR2 in HEK293T cells.
2 to 6 show the activity evaluation results of JAK Protak derivatives in the mast cell line HMC 1.1.
이하, 본 발명을 더욱 상세하게 설명한다. 그러나 본 발명은 여러가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 의해 본 발명이 한정되지 않는다. Hereinafter, the present invention will be described in more detail. However, the present invention can be implemented in many different forms and the present invention is not limited by the embodiments described herein.
본 명세서에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로, 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 발명의 명세서에서 어떤 구성요소를 ‘포함’한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다. Terms used in this specification are only used to describe specific embodiments, and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In the specification of the present invention, 'include' a certain element means that it may further include other elements rather than excluding other elements unless otherwise stated.
본 발명에 있어서 용어 “펩타이드(peptide)”는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미하는 것일 수 있다. In the present invention, the term “peptide” may refer to a linear molecule formed by binding amino acid residues to each other through a peptide bond.
본 발명에서 용어 “프로탁”은 단백질 가수분해 표적화 키메라(proteolysis targeting chimera)로, 표적 단백질의 리간드와 유비퀴틴 리가아제에 결합하는 리간드가 링커를 통해 연결된 이종이량체 분자이다. 본 발명에서 JAK 단백질 결합 도메인과 유비퀴틴 리가아제 결합 도메인이 링커 도메인으로 연결된 형태의 JAK 프로탁 키메라 분자는 두 개의 단백질 도메인이 각각의 기능을 유지하면서 링커를 통해 연결된 융합 단백질 형태이다. In the present invention, the term “Protak” is a proteolysis targeting chimera, which is a heterodimeric molecule in which a ligand of a target protein and a ligand binding to ubiquitin ligase are connected through a linker. In the present invention, the JAK protak chimera molecule in which the JAK protein binding domain and the ubiquitin ligase binding domain are linked by a linker domain is a fusion protein in which the two protein domains are linked through a linker while maintaining their respective functions.
용어 "키메라 분자"는 일반적으로 지칭하는 분자가 2종 이상의 서로 다른 도메인 또는 구조로 만들어지되 이들이 자연계에서 함께 단일 분자로 발견되지 않는 것을 의미한다.The term "chimeric molecule" generally refers to a molecule made up of two or more different domains or structures that are not found together as a single molecule in nature.
본 발명에서 용어 "유도체"란, 본 발명의 펩타이드의 N-말단, C-말단 등이 화학적으로 수식되거나 또는 아미노산이 추가되어 변형된 펩타이드를 의미하는 것일 수 있으나, 이에 한정되는 것은 아니고 본 발명의 펩타이드와 동일하거나 유사한 기능을 수행하는 펩타이드를 의미하는 것일 수 있다.The term "derivative" in the present invention may mean a peptide modified by chemically modifying the N-terminus or C-terminus of the peptide of the present invention or by adding amino acids, but is not limited thereto. It may mean a peptide that performs the same or similar function as the peptide.
발명에 있어서 펩타이드는 고체상 합성법 (Solid phase peptide synthesis)을 이용하여 화학적 직접 합성하는 방법, 자동 합성기를 이용하여 합성하는 방법, 펩타이드를 암호화하는 염기서열을 벡터에 삽입하고 발현시켜 제조하는 것일 수 있으나, 이에 한정되는 것은 아니다. In the present invention, the peptide may be prepared by direct chemical synthesis using solid phase peptide synthesis, synthesis using an automatic synthesizer, or by inserting a base sequence encoding the peptide into a vector and expressing it. It is not limited to this.
본 발명에 따른 프로탁 키메라 분자에서 유비퀴틴 리가아제 결합 도메인은 E3 유비퀴틴 리가아제에 결합하는 것으로, E3 유비퀴틴 리가아제는 세레블론(Cereblon) E3 리가아제, ubiquitin-protein ligase E3 component n-recognin 1 (UBR1), ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) 또는 ubiquitin-protein ligase E3 component n-recognin 4 (UBR4)일 수 있다. In the protac chimera molecule according to the present invention, the ubiquitin ligase binding domain binds to E3 ubiquitin ligase, and the E3 ubiquitin ligase is Cereblon E3 ligase, ubiquitin-protein ligase E3 component n-recognin 1 (UBR1) ), ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) or ubiquitin-protein ligase E3 component n-recognin 4 (UBR4).
본 발명에 따른 프로탁 키메라 분자에서 JAK 단백질 결합 도메인과 유비퀴틴 리가아제 결합 도메인은 링커를 통해 서로 결합되고, 링커는 상기 단백질 결합 도메인과 유비퀴틴 리가아제 결합 도메인을 직접/간접, 공유/비공유적으로, 가요성/비가요성으로 연결될 수 있고 링커 도메인은 유비퀴틴 리가아제와 표적 단백질을 효과적으로 가까이 위치시킬 수 있는 정도의 길이로 할 수 있다. 당해 기술 분야의 당업자라면 당해 기술분야에서 일반적으로 공지된 다양한 종류의 링커들이 본 발명에 따른 키메라 분자에 사용될 수 있음을 쉽게 알 수 있을 것이다. 본 발명의 일 실시예에서 상기 유비퀴틴 리가아제 결합 도메인으로 -(Arg)10- 와 링커 -Ahx-Ahx-를 결합하여 JAK 프로탁 키메릭 분자를 제작하였으나, 이에 한정하지 않고 당해 기술분야의 당업자라면 쉽게 선택 가능할 수 있는 공지된 다양한 유비퀴틴 리가아제 결합 도메인과 링커를 사용할 수 있다. In the protac chimera molecule according to the present invention, the JAK protein binding domain and the ubiquitin ligase binding domain are bonded to each other through a linker, and the linker connects the protein binding domain and the ubiquitin ligase binding domain directly/indirectly, covalently/non-covalently, It can be connected in a flexible / inflexible manner, and the linker domain can be of a length sufficient to effectively position the ubiquitin ligase and the target protein in close proximity. A person skilled in the art will readily recognize that various types of linkers commonly known in the art can be used in the chimeric molecules according to the present invention. In one embodiment of the present invention, a JAK protak chimeric molecule was prepared by combining -(Arg) 10 - and a linker -Ahx-Ahx- with the ubiquitin ligase binding domain, but it is not limited thereto, and those skilled in the art A variety of known ubiquitin ligase binding domains and linkers that can be readily selected can be used.
본 발명에서 제작된 JAK 펩타이드 프로탁 유도체 및 물리화학적 특성은 아래 표 1에 나타난 바와 같다. The JAK peptide protac derivatives and physicochemical properties prepared in the present invention are shown in Table 1 below.
(m/z) MS
( m/z)
(Rt : min)HPLC
(R t : min)
3777.552[M+H] + :
3777.552
3659.189[M+H] + :
3659.189
3650.413[M+H] + :
3650.413
4131.394[M+H] + :
4131.394
3722.430[M+H] + :
3722.430
3793.355[M+H] + :
3793.355
4320.03[M+H] + :
4320.03
3554.57[M] + :
3554.57
4052.52[M+H] + :
4052.52
4284.475[M+H] + :
4284.475
4389[M+Na] + :
4389
4343.503[M+H] + :
4343.503
4511.360[M] + :
4511.360
4020.339[M+H] + :
4020.339
4011.487[M+H] + :
4011.487
상기 표에서 프로탁 JAKPP 4, JAKPP 14 및 JAKPP 15는 URB에 대한 결합력 확인을 위한 풀다운 어세이에서 사용하기 위해 제작하였다. JAKPP 5와 JAKPP 6은 펩타이드의 반감기가 증가될 수 있게 N 말단에 C-C 공유결합을 포함하도록 제작하였다. JAKPP 1 내지 6은 JAK2를 표적단백질로 하는 프로탁 서열이고 그 중에서 JAKPP 5가 JAK2 단백질을 분해하는 데 가장 효과가 좋게 나타났다. In the above table,
JAKPP 7 및 JAKPP 8은 JAK1을 표적단백질로 하고 JAKPP 9는 JAK3을 표적단백질로 하여 서열을 제작하였고, 프로탁 JAKPP 7을 변형하여 JAKPP 10 내지 JAKPP 13을 제작하였다. 효과에 있어서프로탁 JAKPP 9는 JAK3 표적 단백질로 서열을 제작하였기에 JAK3 단백질 분해에 효과적이고, JAKPP 12은 JAK1단백질을 분해하는 데 효과적이었다.
상기 JAK 프로탁을 제작하는 데 사용한 서열을 서열번호 1 내지 18로 정하였다.Sequences used to construct the JAK Protak were set as SEQ ID NOs: 1 to 18.
본 발명에 따라 JAK 프로탁 키메라 분자의 유비퀴틴 리가아제 결합 도메인이 E3 유비퀴틴 리가아제와 결합하고 단백질 결합 도메인이 JAK 펩타이드와 결합하여 가까이 위치하게 되면, 표적 단백질이 유비퀴틴 리가아제에 의해 인식되어 상기 단백질의 유비퀴틴화 및 프로테아좀에 의한 분해 과정을 거치게 된다. According to the present invention, when the ubiquitin ligase-binding domain of the JAK protac chimera molecule binds to E3 ubiquitin ligase and the protein-binding domain binds to the JAK peptide and is located close to it, the target protein is recognized by the ubiquitin ligase and the protein is It undergoes ubiquitination and degradation by the proteasome.
본 발명의 조성물은 투여를 위하여, 약학적으로 허용가능한 염, 담체, 부형제, 희석제, 가용화제 등을 포함할 수 있다. 상기 약학적으로 허용가능한 염은 제약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 나트륨, 칼륨, 칼슘, 마그네슘, 리튬, 구리, 망간, 아연, 철 등을 비롯한 무기이온의 염과 염산, 인산, 황산과 같은 무기산의 염이 있으며, 그 외에 아스코르브산, 시트르산, 타르타르산, 락트산, 말레산, 말론산, 푸마르산, 글리콜산, 숙신산, 프로피온산, 아세트산, 오로테이트산, 아세틸살리실산과 같은 유기산의 염 등과 라이신, 아르기닌, 구아 니딘 등의 아미노산 염이 있다. 또한 약학적인 반응, 정제 및 분리과정에서 사용될 수 있는 테트라메틸 암모늄, 테트라에틸 암모늄, 테트라프로필 암모늄, 테트라부틸 암모늄, 벤질 트리메틸 암모늄, 벤제토늄 등의 유기이온의 염이 있다. 다만, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 상기 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티 톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있고, 가용화제로는 폴록사머 및 라브라솔 등을 들 수 있으나, 이에 제한되지 않는다. For administration, the composition of the present invention may include pharmaceutically acceptable salts, carriers, excipients, diluents, solubilizers, and the like. The pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, and includes, for example, sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, iron and salts of inorganic ions and hydrochloric acid, There are salts of inorganic acids such as phosphoric acid and sulfuric acid, as well as salts of organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotate acid, and acetylsalicylic acid. and amino acid salts such as lysine, arginine, and guanidine. In addition, there are organic ion salts such as tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, benzyl trimethyl ammonium, and benzethonium that can be used in pharmaceutical reactions, purification and separation processes. However, the types of salts meant in the present invention are not limited by these listed salts. The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline quality cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, and solubilizing agents include poloxamer and labrasol; Not limited to this.
본 발명의 약학 조성물은 당업계에 잘 알려진 방법을 사용하여 약학적 제형으로 제조될 수 있다. 제형의 제조에 있어서, 활성 성분을 담체와 함께 혼합 또는 희석하거나, 용기 형태의 담체 내에 봉입시킬 수 있다. 본 발명의 약학 조성물을 경구 투여용 제형으로 제조할 경우, 예를 들어 정제, 트로키제, 로렌지, 수용성 또는 유성현탁액, 조제분말 또는 과립, 에멀젼, 하드 또는 소프트 캡슐, 시럽 또는 엘릭시르제로 제제화할수 있다. 상기 약학 조성물은 경구, 직장, 경피, 정맥 내, 근육 내, 복강 내, 골수 내, 경막 내 또는 피하로 투여될 수 있다. 경구 투여를 위한 제형은 정제, 환제, 연질 또는 경질 캅셀제, 과립제, 산제, 액제 또는 유탁제일 수 있 으나, 이에 한정되는 것은 아니다. 비경구 투여를 위한 제형은 주사제, 점적제, 로션, 연고, 겔, 크림, 현탁제, 유제, 좌제, 패취 또는 분무제일 수 있으나, 이에 한정되는 것은 아니다. 상기 약학 조성물은 필요에 따라 희석제, 부형제, 활택제, 결합제, 붕해제, 완충제, 분산제, 계면 활성제, 착색제, 향료 또는 감미제 등의 첨가제를 포함할 수 있다.The pharmaceutical composition of the present invention can be prepared into a pharmaceutical formulation using methods well known in the art. In preparation of the formulation, the active ingredient may be mixed or diluted with a carrier, or encapsulated in a carrier in the form of a container. When the pharmaceutical composition of the present invention is prepared as a dosage form for oral administration, for example, it can be formulated into tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs. . The pharmaceutical composition may be administered orally, rectally, transdermally, intravenously, intramuscularly, intraperitoneally, intramedullarily, intrathecally or subcutaneously. Formulations for oral administration may be tablets, pills, soft or hard capsules, granules, powders, solutions or emulsions, but are not limited thereto. Formulations for parenteral administration may be injections, drops, lotions, ointments, gels, creams, suspensions, emulsions, suppositories, patches or sprays, but are not limited thereto. The pharmaceutical composition may include additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, coloring agents, flavoring agents, or sweeteners, if necessary.
이하 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본 발명의 실시예에 대하여 상세히 설명한다. 그러나 본 발명은 여러가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments described herein.
세포의 준비preparation of cells
사람 신장세포주 HEK293T세포는 10% 소태아혈청(fetal bovine serum (FBS, HyClone))과 1% 항생제가 첨가된 Dulbecco’s Modified Eagle Medium(DMEM, HyClone)을 사용하였고, 사람 비만세포주 HMC 1.1세포는 10% FBS과 1% 항생제가 첨가된 Iscove's Modified Dulbecco's Medium(IMDM, HyClone)을 사용하여 5% CO2와 37 ℃가 유지되는 항온기에서 배양하였다. 그 후HEK293T 세포에 2 μg의 UBR1(pcDNA3.1-hUBR1-his6) 또는 UBR2(pcDNA3.1-hUBR2-his6) 플라스미드를 형질감염 시약(Roche)을 이용하여 형질감염하였다. Dulbecco's Modified Eagle Medium (DMEM, HyClone) supplemented with 10% fetal bovine serum (FBS, HyClone) and 1% antibiotics was used for the human kidney cell line HEK293T cells, and for the human mast cell line HMC 1.1 cells, 10% FBS and 1% antibiotics were added using Iscove's Modified Dulbecco's Medium (IMDM, HyClone) and cultured in an incubator maintained at 5% CO 2 and 37 °C. Then, 2 μg of UBR1 (pcDNA3.1-hUBR1-his6) or UBR2 (pcDNA3.1-hUBR2-his6) plasmid was transfected into HEK293T cells using a transfection reagent (Roche).
단백질의 풀다운 어세이(pull down assay) Protein pull down assay
JAKPP 4, JAKPP 14 및 JAKPP 15를 각각 대용량 스트렙타비딘 아가로겔(streptavidin agarose resin(Thermo))에 결합시켰다. UBR1과 UBR2로 형질감염된 HEK293T 세포 추출물 300 μg에 JAKPP 4가 결합된 스트렙타비딘 아가로스겔, JAKPP 14가 결합된 스트렙타비딘 아가로스겔, JAKPP 15가 결합된 스트렙타비딘 아가로스겔을 넣어 4 ℃에서 3시간 반응시켰다. 반응 후 일차원 전기 이동을 위해 시료를 제조하였다.
Cycloheximide(CHX) 처리Cycloheximide (CHX) treatment
사이클로헥사미드(cycloheximide, CHX(Calbiochem))는 배양배지에 200 μg/mL이 되도록 희석하였다. 비부착형 세포인 HMC 1.1세포는 세포가 80% 정도 채워진 배양 플라스크의 세포를 원심분리한 후 2.5 x 105개를 200 μg/mL의 CHX를 포함하는 IMDM배지(10% FBS, 1% antibiotics) 3 mL에서 1시간 이상 배양하였다.Cycloheximide (CHX (Calbiochem)) was diluted to 200 μg/mL in the culture medium. HMC 1.1 cells, which are non-adherent cells, were centrifuged from cells in a culture flask filled to about 80%, and then 2.5 x 10 5 were placed in IMDM medium containing 200 μg/mL of CHX (10% FBS, 1% antibiotics). Incubated for more than 1 hour in 3 mL.
JAK-프로탁 펩타이드의 처리Treatment of JAK-Protac Peptide
JAK-프로탁 펩타이드를 3차 증류수에 10 mM의 농도로 제조하였다. 각각의 10 mM JAK-프로탁 펩타이드 스탁 솔루션을 CHX가 전처리된 HMC 1.1세포에 10 μM, 25 μM, 30 μM, 50 μM 또는 90 μM이 되도록 처리하고 사용된 JAK-프로탁 펩타이드에 따라6시간, 12 시간 또는 24 시간 동안 배양하였다. 사용된 JAK-프로탁 펩타이드 서열은 상기 표 1 및 2에 기재된 것과 같다. JAK-protak peptide was prepared at a concentration of 10 mM in tertiary distilled water. Each 10 mM JAK-Protak peptide stock solution was treated with CHX-pretreated HMC 1.1 cells at concentrations of 10 μM, 25 μM, 30 μM, 50 μM or 90 μM and incubated for 6 hours, depending on the JAK-Protak peptide used. Incubated for 12 or 24 hours. The JAK-Protak peptide sequence used is as described in Tables 1 and 2 above.
세포의 수확harvesting of cells
원심분리(2,000 xg, 5 min)하여 배지를 제거한 후 Dulbecco’s phosphate buffered saline(DPBS, WelGENE)으로 1회 세척 후 원심분리하여 세포를 수확하였다.After removing the medium by centrifugation (2,000 xg, 5 min), cells were harvested by centrifugation after washing once with Dulbecco's phosphate buffered saline (DPBS, WelGENE).
세포 내 JAK 펩타이드 분해 확인을 위한 시료 제조Sample preparation to confirm intracellular JAK peptide degradation
수확한 세포에 단백질분해효소 억제제 칵테일(Protease inhibitor cocktail(Cell signaling))을 포함한 RIPA 완충용액(20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1% NP-40, 1% sodium deoxycholate)을 첨가하고 vortex로 세포를 균일하게 풀어준 후 4 ℃ 조건을 유지하며 초음파 분쇄기로 분쇄하였다. 분쇄 후 14,000 xg에서 30분 동안 원심분리하고 상층액을 취하여 BCA(Thermo Fisher scientific)방법으로 단백질을 정량하여 세포 추출물의 단백질 농도가 1~2 mg/ml이 되게 하였다. 세포추출물 20 μL(2 mg/ml)을 5X 일차원 SDS-PAGE용 완충용액(0.5M Tris-HCl, pH 6.8, 10% SDS, 10% β-mercaptoethanol, 30% glycerol, 0.2% bromophenol blue) 5 μL과 혼합하여 95 ℃에서 5분간 가열하였다.RIPA buffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1% NP-40, 1% NP-40, 1% sodium deoxycholate) was added, the cells were uniformly released by vortex, and then the cells were pulverized with a sonicator while maintaining the condition of 4 ℃. After grinding, centrifugation was performed at 14,000 xg for 30 minutes, the supernatant was taken, and protein was quantified by a BCA (Thermo Fisher scientific) method so that the protein concentration of the cell extract was 1-2 mg/ml. 20 μL (2 mg/ml) of cell extract was mixed with 5 μL of 5X one-dimensional SDS-PAGE buffer (0.5M Tris-HCl, pH 6.8, 10% SDS, 10% β-mercaptoethanol, 30% glycerol, 0.2% bromophenol blue) and heated at 95 °C for 5 minutes.
일차원 전기 이동one-dimensional electrophoresis
아크릴-비스 아크릴아미드 용액(40%, 29:1, v/v)을 사용하여 1.0 mm 또는 1.5 mm 두께의 8 % 또는 12 % 아크릴아미드 분리용 겔(pH 8.8)을 만들고, 그 위에 5% 스태킹 겔(pH 6.8)을 만들어 사용하였다. 스태킹 겔의 웰은 15웰을 사용하여 25 μg의 단백질 시료를 가하였다. 70~80 V/hr로 스태킹한 후 150~180 V/hr로 JAK2 단백질 위치를 구별할 수 있을 때까지 분리하였다.A 1.0 mm or 1.5 mm thick 8% or 12% acrylamide separation gel (pH 8.8) was prepared using an acryl-bis acrylamide solution (40%, 29:1, v/v), on which 5% was stacked. A gel (pH 6.8) was made and used. 25 μg of protein sample was added using 15 wells of the stacking gel. After stacking at 70-80 V/hr, separation was performed at 150-180 V/hr until the JAK2 protein location could be distinguished.
웨스톤블롯(Western blot)Western blot
전기영동 후 분리된 단백질을 Polyvinylidene fluoride(PVDF) 멤브레인으로 60 V/hr에서 100분 동안 전기이동 하였다. 단백질을 전기이동한 PVDF 멤브레인은 5% bovine serum albumin(BSA)이 포함된 1X TBS-T 완충용액(25 mM Tris, 150 mM NaCl, 0.1% tween-20, pH 7.4)에 1시간 블로킹한 후 동일한 완충용액에 각 항체를 희석하여 4 ℃에서 12시간 반응하였다. UBR1 항체(abCam, ab138267)는 1000:1로 희석하여 사용하였고 UBR2 항체는(Bioworld, BS60150)는 1000:1로 희석하여 사용하였다. JAK2 항체(Cell signaling, 3230S)는 500:1로 희석하여 사용하였고 β-Actin 항체(Cell signaling, 3700S)는 1000:1로 희석하여 사용하였다. 1차 항체 반응 후 1X TBS-T로 5분씩 5회 세척하였다. 2차 항체는 horseradish peroxidase(HRP)가 결합된 anti-rabbit 항체 또는 anti-mouse 항체를 5% BSA를 포함하는 1X-TBS-에 2000:1로 희석하여 실온에서 1시간 이상 반응시켰다. 반응 후, 1차 항체 세척과정과 동일하게 세척하였다. 발색을 위해 ECL(Pierce) 용액을 넣어 Imager (Odyssey, LI-COR 2800-00)를 이용하여 발색 하였다.After electrophoresis, the separated proteins were electrophoresed through a polyvinylidene fluoride (PVDF) membrane at 60 V/hr for 100 minutes. The PVDF membrane on which the protein was electrophoresed was blocked in 1X TBS-T buffer solution (25 mM Tris, 150 mM NaCl, 0.1% tween-20, pH 7.4) containing 5% bovine serum albumin (BSA) for 1 hour, and then the same Each antibody was diluted in a buffer solution and reacted at 4° C. for 12 hours. The UBR1 antibody (abCam, ab138267) was used at a dilution of 1000:1, and the UBR2 antibody (Bioworld, BS60150) was used at a dilution of 1000:1. JAK2 antibody (Cell signaling, 3230S) was diluted 500:1, and β-Actin antibody (Cell signaling, 3700S) was diluted 1000:1. After the primary antibody reaction, the cells were washed 5 times for 5 minutes each with 1X TBS-T. For the secondary antibody, horseradish peroxidase (HRP)-coupled anti-rabbit antibody or anti-mouse antibody was diluted 2000:1 in 1X-TBS- containing 5% BSA and reacted at room temperature for 1 hour or longer. After the reaction, washing was performed in the same manner as in the primary antibody washing process. For color development, ECL (Pierce) solution was put in and color developed using an Imager (Odyssey, LI-COR 2800-00).
실시예 1. UBR1 또는 UBR2의 결합력 확인Example 1. Confirmation of binding force of UBR1 or UBR2
HEK293T 세포에서JAKPP 4, JAKPP 14 및 JAKPP 15와 UBR1, UBR2의 풀다운 어세이 결과를 확인하였다. HEK293T 세포 추출물 300 μg을 JAK2-프로탁(JAKPP 4, JAKPP 14 및 JAKPP 15)이 결합된 스트렙타비딘 아가로스겔로 4 ℃에서 3시간 동안 배양하였다. 레진에 결합된 단백질 샘플을 SDS-PAGE 겔 이후 UBR1, UBR2에 특이적인 항체로 면역블롯 분석을 수행하였다. The pull-down assay results of
그 결과, UBR1에 대하여 JAKPP 4가 JAKPP 14 및 JAKPP 15에 비해 2배 이상 강하게 결합하는 것을 확인하였다. 그러나, UBR2에는 JAKPP 4, JAKPP 14 및 JAKPP 15의 결합 정도에 차이가 없었다(도 1). 도 1의 화살표는 UBR 1, UBR2를 각각 나타내고 Input 2%는 HEK293T cell crude extract 60 μg, Input 1%은 HEK293T cell crude extract 30 μg을 나타낸다. As a result, it was confirmed that
실시예 2. 비만세포주에서의 JAK2-프로탁의 효과 확인Example 2. Confirmation of the effect of JAK2-Protak in mast cell lines
2-1. JAKPP 4, JAKPP 14 및 JAKPP 15의 효능 평가 2-1. Efficacy evaluation of
비만 세포주인 HMC 1.1에서 JAKPP 4, JAKPP 14 및 JAKPP 15의 활성 평가 결과를 확인하였다. JAK2-프로탁(JAKPP 4, JAKPP 14 및 JAKPP 15)이 각각 10μM 또는 30μM으로 존재하는 조건과 존재하지 않는 조건에서 HMC1.1 세포를 사이클로헥사미드 200 μg/mL으로 6시간 동안 처리하였다. 세포 추출물(25 μg)을 SDS-PAGE 겔 후 JAK2 또는 β-Actin 특이적인 항체로 면역블롯을 수행하였다. The activity evaluation results of
그 결과, 30 μM의 JAKPP 4를 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK2 단백질이 80% 이상 감소되는 것을 확인하였다(도 2). 도 2에서 화살표는 JAK2, β-Actin을 나타내고 Veh 은 vehicle을 나타낸다.As a result, it was confirmed that the JAK2 protein present in the human mast cell line HMC1.1 was reduced by more than 80% when treated with 30 μM of JAKPP 4 (FIG. 2). In FIG. 2, arrows indicate JAK2 and β-Actin and Veh indicates vehicle.
2-2. JAKPP 1, JAKPP 2 및 JAKPP 3의 효능 평가2-2. Efficacy evaluation of
비만 세포주 HMC 1.1에서 JAKPP 1, JAKPP 2 및 JAKPP 3의 활성 평가 결과를 확인하였다. JAK2-프로탁(JAKPP 1, JAKPP 2 및 JAKPP 3)이 각각10 μM 또는 90 μM으로 존재하는 조건과 존재하지 않는 조건에서 HMC1.1 세포를 사이클로헥사미드 200 μg/mL으로 12 시간 동안 처리하였다. 세포 추출물(50 μg)을 SDS-PAGE 겔 후 JAK2 또는 β-Actin 특이적인 항체로 면역블롯을 수행하였다. The activity evaluation results of
그 결과, 90 μM의 JAKPP 1을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK2 단백질이 10% 정도 감소되는 것을 확인하였다. 또한, 90 μM의 JAKPP 2을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK2 단백질이 30% 정도 감소되는 것을 확인하였다(도 3). 도 3에서 화살표는 JAK2, β-Actin을 나타내고 Veh 은 vehicle을 나타낸다.As a result, it was confirmed that JAK2 protein present in the human mast cell line HMC1.1 was reduced by about 10% when 90 μM of
2-3. JAKPP 1, JAKPP 4, JAKPP 5 및 JAKPP 6의 효능 평가2-3. Efficacy evaluation of
비만 세포주 HMC 1.1에서 JAKPP 1, JAKPP 4, JAKPP 5 및 JAKPP 6의 활성 평가 결과를 확인하였다. JAK2-프로탁(JAKPP 1, JAKPP 4, JAKPP 5 및 JAKPP 6)이 각각 10 μM 또는 30 μM으로 존재하는 조건과 존재하지 않는 조건에서 HMC1.1 세포를 사이클로헥사미드 200 μg/mL으로 24시간 동안 처리하였다. 세포 추출물(25 μg)을 SDS-PAGE 겔 후 JAK2 또는 β-Actin 특이적인 항체로 면역블롯을 수행하였다.
그 결과, 30 μM의 JAKPP 1 또는 30 μM의 JAKPP 4을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK2 단백질이 각각 30% 이상 감소되는 것을 확인하였다. 또한, 30 μM의 JAKPP 5을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK2 단백질이 50% 이상 감소되는 것을 확인하였다(도 4). 도 4에서 화살표는 JAK2, β-Actin을 나타내고 Veh 은 vehicle을 나타낸다.As a result, it was confirmed that JAK2 protein present in the human mast cell line HMC1.1 was reduced by more than 30% when treated with 30 μM of
실시예 3. 비만세포주에서 JAK1-프로탁, JAK3-프로탁의 효과 확인Example 3. Confirmation of the effects of JAK1-protak and JAK3-protak in mast cell lines
3-1. JAKPP 7, JAKPP 8및 JAKPP 9의 효능 평가3-1. Efficacy evaluation of
비만 세포주 HMC 1.1에서 JAKPP 7, JAKPP 8및 JAKPP 9의 활성 평가 결과를 확인하였다. JAK-프로탁(JAKPP 7, JAKPP 8및 JAKPP 9)이 각각 25 μM으로 존재하는 조건과 존재하지 않는 조건에서 HMC1.1 세포를 사이클로헥사미드 200 μg/mL으로 24시간 동안 처리하였다. 세포 추출물(20 μg)을 SDS-PAGE 겔 후 JAK1, JAK3 또는 β-Actin 특이적인 항체로 면역블롯을 수행하였다.The activity evaluation results of
그 결과, 25 μM의 JAKPP 7을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK1 단백질이 15% 정도 감소하였으며 JAK3 단백질이 90% 이상 감소되는 것을 확인하였다. 또한, 25 μM의 JAKPP 9를 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK3 단백질이 90% 이상 감소되는 것을 확인하였다(도 5). 도 5에서 화살표는 JAK1, JAK3 또는 β-Actin를 나타내고 Veh 은 vehicle을 나타낸다.As a result, it was confirmed that when 25 μM of
3-2. JAKPP 10, JAKPP 11, JAKPP 12 및 JAKPP 13의 효능 평가3-2. Efficacy evaluation of
비만 세포주 HMC 1.1에서 JAKPP 10, JAKPP 11, JAKPP 12 및 JAKPP 13의 활성 평가 결과를 확인하였다. JAK-프로탁(JAKPP 10, JAKPP 11, JAKPP 12 및 JAKPP 13)이 각각 25 μM 또는 50 μM으로 존재하는 조건과 존재하지 않는 조건에서 HMC1.1 세포를 사이클로헥사미드 200 μg/mL으로 24시간 동안 처리하였다. 세포 추출물(20 μg)을 SDS-PAGE 겔 후 JAK1, JAK2 또는 β-Actin 특이적인 항체로 면역블롯을 수행하였다.The activity evaluation results of
그 결과, 50 μM의 JAKPP 12을 처리하였을 때 사람 비만 세포주인 HMC1.1에 존재하는 JAK1 단백질이 70% 감소하고 또는 50 μM JAKPP 13을 처리한 경우 JAK1 단백질이 40% 감소되는 것을 확인하였다. 한편 같은 조건에서 JAK2 단백질은 감소되지 않았다(도 6). 도 6에서 화살표는 JAK1 또는 JAK2 또는 β-Actin를 나타내고 Veh 은 vehicle을 나타낸다.As a result, it was confirmed that the JAK1 protein present in the human mast cell line HMC1.1 was reduced by 70% when treated with 50 μM JAKPP 12, or by 40% when treated with 50 μM JAKPP 13. Meanwhile, JAK2 protein was not reduced under the same conditions (FIG. 6). In FIG. 6, arrows indicate JAK1 or JAK2 or β-Actin and Veh indicates vehicle.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.
<110> Azcuris Co., Ltd. <120> JAK PROTAC chimeric molecule and Pharmaceutical composition for treatment of disease involving JAK peptide <130> P20220053KR <150> KR 10-2021-0071015 <151> 2021-06-01 <160> 18 <170> KoPatentIn 3.0 <210> 1 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> JAK protein binding domain sequence <400> 1 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn 1 5 10 <210> 2 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 2- protein binding domain sequence <400> 2 Lys Gln Lys Ile Trp Pro Gly Ile Pro Ser Pro Glu Ser Glu Phe Glu 1 5 10 15 <210> 3 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 3- protein binding domain sequence <400> 3 Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe Phe 1 5 10 15 <210> 4 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 1- protein binding domain sequence <400> 4 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser Trp 1 5 10 15 <210> 5 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 4- protein binding domain sequence <400> 5 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser Trp 1 5 10 15 Lys <210> 6 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 5- protein binding domain sequence <400> 6 Cys Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser 1 5 10 15 Trp <210> 7 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 6- protein binding domain sequence <400> 7 Cys Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Ala Ser 1 5 10 15 Trp Cys <210> 8 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> JAK protein binding domain sequence <400> 8 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg 1 5 10 <210> 9 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 8- protein binding domain sequence <400> 9 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser 1 5 10 <210> 10 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 9- protein binding domain sequence <400> 10 Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro Arg Ile Pro Thr 1 5 10 15 Leu Lys <210> 11 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 7- protein binding domain sequence <400> 11 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Lys Lys Leu Pro Ser 1 5 10 15 Val Leu Leu Phe Lys 20 <210> 12 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 10- protein binding domain sequence <400> 12 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Ala Leu Asp Phe Ser 20 <210> 13 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 11- protein binding domain sequence <400> 13 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Arg Leu Asp Phe Ser 20 <210> 14 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> JAK protein binding domain sequence <400> 14 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg 1 5 10 <210> 15 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 12- protein binding domain sequence <400> 15 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Ala Leu Asp Phe Ser 20 <210> 16 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 13- protein binding domain sequence <400> 16 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg Lys Lys Lys Pro Arg 1 5 10 15 Arg Leu Lys Phe Ser 20 <210> 17 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 14- protein binding domain sequence <400> 17 Lys Gln Lys Ile Trp Pro Gly Ile Pro Ser Pro Glu Ser Glu Phe Glu 1 5 10 15 Lys <210> 18 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> JAKPP 15- protein binding domain sequence <400> 18 Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe Phe 1 5 10 15 Lys <110> Azcuris Co., Ltd. <120> JAK PROTAC chimeric molecule and Pharmaceutical composition for treatment of disease involving JAK peptide <130> P20220053KR <150> KR 10-2021-0071015 <151> 2021-06-01 <160> 18 <170> KoPatentIn 3.0 <210> 1 <211> 13 <212> PRT <213> artificial sequence <220> <223> JAK protein binding domain sequence <400> 1 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn 1 5 10 <210> 2 <211> 16 <212> PRT <213> artificial sequence <220> <223> JAKPP 2-protein binding domain sequence <400> 2 Lys Gln Lys Ile Trp Pro Gly Ile Pro Ser Pro Glu Ser Glu Phe Glu 1 5 10 15 <210> 3 <211> 16 <212> PRT <213> artificial sequence <220> <223> JAKPP 3-protein binding domain sequence <400> 3 Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe Phe 1 5 10 15 <210> 4 <211> 16 <212> PRT <213> artificial sequence <220> <223> JAKPP 1-protein binding domain sequence <400> 4 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser Trp 1 5 10 15 <210> 5 <211> 17 <212> PRT <213> artificial sequence <220> <223> JAKPP 4-protein binding domain sequence <400> 5 Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser Trp 1 5 10 15 Lys <210> 6 <211> 17 <212> PRT <213> artificial sequence <220> <223> JAKPP 5-protein binding domain sequence <400> 6 Cys Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Cys Ser 1 5 10 15 Trp <210> 7 <211> 18 <212> PRT <213> artificial sequence <220> <223> JAKPP 6-protein binding domain sequence <400> 7 Cys Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn Ala Ser 1 5 10 15 Trp Cys <210> 8 <211> 11 <212> PRT <213> artificial sequence <220> <223> JAK protein binding domain sequence <400> 8 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg 1 5 10 <210> 9 <211> 14 <212> PRT <213> artificial sequence <220> <223> JAKPP 8-protein binding domain sequence <400> 9 Trp Phe Gln Arg Ala Lys Met Pro Arg Ala Leu Asp Phe Ser 1 5 10 <210> 10 <211> 18 <212> PRT <213> artificial sequence <220> <223> JAKPP 9-protein binding domain sequence <400> 10 Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro Arg Ile Pro Thr 1 5 10 15 Leu Lys <210> 11 <211> 21 <212> PRT <213> artificial sequence <220> <223> JAKPP 7-protein binding domain sequence <400> 11 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Lys Lys Leu Pro Ser 1 5 10 15 Val Leu Leu Phe Lys 20 <210> 12 <211> 21 <212> PRT <213> artificial sequence <220> <223> JAKPP 10-protein binding domain sequence <400> 12 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Ala Leu Asp Phe Ser 20 <210> 13 <211> 21 <212> PRT <213> artificial sequence <220> <223> JAKPP 11- protein binding domain sequence <400> 13 Lys Thr Leu Met Gly Asn Pro Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Arg Leu Asp Phe Ser 20 <210> 14 <211> 11 <212> PRT <213> artificial sequence <220> <223> JAK protein binding domain sequence <400> 14 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg 1 5 10 <210> 15 <211> 21 <212> PRT <213> artificial sequence <220> <223> JAKPP 12-protein binding domain sequence <400> 15 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg Ala Lys Met Pro Arg 1 5 10 15 Ala Leu Asp Phe Ser 20 <210> 16 <211> 21 <212> PRT <213> artificial sequence <220> <223> JAKPP 13- protein binding domain sequence <400> 16 Lys Thr Leu Met Gly Asn Arg Trp Phe Gln Arg Lys Lys Lys Pro Arg 1 5 10 15 Arg Leu Lys Phe Ser 20 <210> 17 <211> 17 <212> PRT <213> artificial sequence <220> <223> JAKPP 14-protein binding domain sequence <400> 17 Lys Gln Lys Ile Trp Pro Gly Ile Pro Ser Pro Glu Ser Glu Phe Glu 1 5 10 15 Lys <210> 18 <211> 17 <212> PRT <213> artificial sequence <220> <223> JAKPP 15-protein binding domain sequence <400> 18 Lys Lys Phe Leu Ile Pro Ser Val Pro Asp Pro Lys Ser Ile Phe Phe 1 5 10 15 Lys
Claims (11)
A chimeric molecule comprising a JAK protein binding domain, a ubiquitin ligase binding domain, and a linker domain linked to the ubiquitin ligase binding domain and the protein binding domain.
상기 단백질 결합 도메인은 JAK1 단백질, JAK2 단백질 및 JAK3 단백질로 구성된 군에서 선택되는 어느 하나의 JAK 단백질에 결합하는 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the protein binding domain binds to any one JAK protein selected from the group consisting of JAK1 protein, JAK2 protein and JAK3 protein.
상기 단백질 결합 도메인은 서열번호 1 내지 서열번호 18로 구성된 군에서 선택되는 어느 하나의 아미노산 서열을 포함하는 펩타이드인 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the protein binding domain is a peptide comprising any one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 18.
상기 단백질 결합 도메인은 서열번호 1의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK2 단백질인 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the protein binding domain is a peptide comprising the amino acid sequence of SEQ ID NO: 1, and the JAK protein is a JAK2 protein.
상기 단백질 결합 도메인은 서열번호 8의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK3 단백질인 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the protein binding domain is a peptide comprising the amino acid sequence of SEQ ID NO: 8, and the JAK protein is a JAK3 protein.
상기 단백질 결합 도메인은 서열번호 14의 아미노산 서열을 포함하는 펩타이드이고, 상기 JAK 단백질은 JAK1 단백질인 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the protein binding domain is a peptide comprising the amino acid sequence of SEQ ID NO: 14, and the JAK protein is a JAK1 protein.
상기 유비퀴틴 리가아제 결합 도메인은 E3 유비퀴틴 리가아제에 결합하는 것을 특징으로 하는 키메라 분자.
According to claim 1,
The chimeric molecule, characterized in that the ubiquitin ligase binding domain binds to E3 ubiquitin ligase.
상기 E3 유비퀴틴 리가아제는 UBR1(ubiquitin-protein ligase E3 component n-recognin 1) 또는 UBR2(ubiquitin-protein ligase E3 component n-recognin 2)인 것을 특징으로 하는 키메라 분자.
According to claim 7,
The E3 ubiquitin ligase is a chimeric molecule, characterized in that UBR1 (ubiquitin-protein ligase E3 component n-recognin 1) or UBR2 (ubiquitin-protein ligase E3 component n-recognin 2).
A pharmaceutical composition for treating or preventing a JAK protein-related disease, comprising the chimeric molecule of any one of claims 1 to 8.
상기 약학 조성물은 천식, 알레르기성 피부염, 아토피성 피부염, 건선 및 암으로 구성된 군에서 선택되는 질환의 치료 또는 예방용 약학 조성물.
According to claim 9,
The pharmaceutical composition is a pharmaceutical composition for the treatment or prevention of a disease selected from the group consisting of asthma, allergic dermatitis, atopic dermatitis, psoriasis and cancer.
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