Janssen Pharmaceuticals Submitted Menin/MLL Protein-Protein Interaction Inhibitor Patent

Protein-Protein-protein interaction (PPI)) is the main realization of biological information regulation. It plays a very important role in biological processes and is a key factor in determining cell fate. Scientists have found that many proteins interact with each other, and protein-protein interactions related to human diseases are constantly being discovered through genomics and proteomics. In the role of traditional drugs, drug targets are usually enzymes or receptors, and protein-protein interactions represent a new and important entry point for disease treatment.

Janssen Pharmaceutical Co., Ltd. (Janssen Pharmaceutica) filed a patent application WO2018050686A1 for a new compound.The compound, which is targeted at the Menin/MLL protein, is a protein interaction inhibitor and can be used to treat leukemia and cancer.

Menin/MLLProtein Introduction

Mixed lineage leukemia gene 1, MML1 for shortOr MLL, which belongs to histone lysine-N-methyltransferase 2A(KMT2A), an enzyme responsible for methylating lysine 4(H3K4) in histone H3, and plays an important role in a variety of protein complexes.

Studies have shown that MML1For the maintenance of hematopoietic stem cells as well as BCell development plays an important role, but histone methylation transfer function is not necessary for hematopoiesis. It is known that chromosome ectopic occurs in MLL1 gene. Chromosome ectopic refers to the abnormal shift of a part of chromosome to another chromosome or other position of the chromosome during cell division. The chromosome ectopic of MLL1 gene is obviously related to acute leukemia of all ages.

Leukemia is a cancer that begins in the blood-forming tissues, such as the bone marrow, and produces a large number of abnormal white blood cells that circulate in the blood. Leukemia is divided into acute and chronic two, acute leukemia fierce, the rapid development of the course, the need to take timely and effective treatment. MLL1Acute leukemia caused by genetic ectopic can be classified as lymphoid leukemia, myeloid leukemia, or both phenotypes, accounting for about 5%of adult patients and 70% of underage patients found the existence of MLL1 gene, acute leukemia treatment is still relatively scarce, so there is an urgent need to develop effective treatment drugs.

Contains MLL1Chromosomal ectopic of the gene produces a new chimeric protein that contains normal MLL1The N-terminal sequence of the protein encoded by the gene can interact with many possible chaperone proteins. So far, scientists have found that more than 60 chaperone proteins can form a fusion with the protein encoded by the MLL1 gene, and this fusion is closely related to the formation and development of leukemia.

Multiple endocrine neoplasia 1Type gene encodes a protein (Menin) is a tumor suppressor protein encoded by the MEN1 gene (Multiple Endocrine Neoplasia type 1). Menin protein is expressed in many different types of nuclei and is active at all stages of human development. It can interact with many proteins and is believed to be involved in many cellular processes. At present, it is a proto-oncogene cofactor of MLL fusion protein. MLL can directly bind to LEDGF, while Menin is necessary to stabilize this binding. Menin interacts with two regions of the nitrogen terminal part of MLL to stably bind to LEDGF, while LEDGF is a transcriptional co-activator that plays a role in cancer, autoimmunity and HIV provirus combination. At present, it has been confirmed that the fusion protein formed by Menin and MLL plays an important role in the transformation of proto-oncogenes. In addition, the MLL fusion protein also needs the participation of Menin in the process of maintaining the expression of Hox gene. In addition, the interaction between Menin and MLL fusion protein can lead to acute leukemia. By regulating the expression of homeotypic gene (HOX), the protein complex can lead to the differentiation of hematopoietic stem cells, and then cause MLL translocation leukemia, that is, mixed lineage leukemia.

Many studies have pointed out that there are several classes of small molecule compounds that can occupy MeninMLL on proteinThe discovery of binding pockets that interfere with the interaction between Menin-MLL provides a new idea for the treatment of such cancers and acute leukemia.

Patent situation

Janssen PharmaceuticalsIn this patent a novel class of spiro-Protein-protein interaction inhibitors, 324 co-synthesized in a patentedCompounds, wherein the compound No. 273 reached the nm level with IC50 in the in vitro test.

Summary

Menin/MLLProtein interaction inhibitors are currently valued by many pharmaceutical giants, BayerAlso applied for a class of spiro PPIInhibitor patent. Since 70 percent of childhood acute leukemias present with MLL mutations, the success of these compounds will be a boon for many pediatric patients.

Reference: https://mp.weixin.qq.com/s/LvFKMWRMwsdyRVNL_RrvDw