444287-84-7

Upstream product

• 79-04-9 chloroacetyl chloride 
• 19171-19-8 pomalidomide 
• 19171-18-7 4-NT 
• 641-70-3 3-nitrophthalic acid anhydride 
• 590365-46-1 (RS)-2,6-dioxopiperidin-3-yl-ammonium trifluoroacetate 
• 202271-89-4 (S)-(-)-4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3-dione 

Relevant academic research and scientific papers

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.

Discovery of a PROTAC targeting ALK with in vivo activity

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.

DIMERIC IMMUNO-MODULATORY COMPOUNDS AGAINST CEREBLON-BASED MECHANISMS

Disclosed are small molecules against cereblon to enhance effector T cell function. Methods of making these molecules and methods of using them to treat various disease states are also disclosed.

Fibrin AChE degradation product as well as preparation method and application thereof (by machine translation)

The compound and pharmaceutically acceptable salts thereof AChE can be used for preparing a novel compound, with a III unique IV induction protein degradation mechanism . and the AChE compound and CRBN a pharmaceutically acceptable salt thereof can, be used for preparing, the compound with a unique induction AChE protein degradation, mechanism, and the compound and pharmaceutically. acceptable salts thereof can reduce toxic and side effects of drugs by using difunctional micromolecules in a similar molar amount,AChE. (by machine translation)

ALK-targeted PROTAC and application thereof

The invention relates to ALK-targeted PROTAC and application thereof, and belongs to the technical field of anti-tumor drugs. The invention aims to provide an ALK-targeted PROTAC molecule. The PROTACmolecule has the structural formula which is shown in a formula I. A ligand pomalidomide of CRBN and a derivative of pomalidomide are adopted as a ligand of an E3 ligase, and coupling of an ALK inhibitor LDK378 with the E3 ligase is achieved through linkers of different types and different chain lengths so as to prepare the ALK-targeted PROTAC molecule successfully; through the ALK-targeted PROTACmolecule, target proteins can be targeted effectively, the content of ALK in cells is reduced, and meanwhile, the ALK-targeted PROTAC is characteristics of good anti-tumor activity in vitro and in vivo, low toxicity to normal cells and high efficiency and low toxicity.

Compound for targeted ubiquitin degradation of EGFR protein as well as pharmaceutical composition and application thereof

The invention discloses a compound for targeted ubiquitin degradation of EGFR protein or a pharmaceutically acceptable salt thereof, and also discloses a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and

Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway

As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via “click reaction” to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments.

COMPOSITIONS AND METHODS FOR TREATING CDK4/6-MEDIATED CANCER

Methods for designing heterobifunctional small molecules which selectively degrade/disrupt CDK4/6 and compositions and methods of using such degraders/disruptors to treat CDK4/6-mediated cancer are provided.

Design, Synthesis, Characterization, and In Vitro Evaluation of Isatin-Pomalidomide Hybrids for Cytotoxicity against Multiple Myeloma Cell Lines

Inspired by the concept of molecular hybridization, a series of new isatin-pomalidomide hybrids (9a–9g) were designed, synthesized, characterized, and evaluated for in vitro cytotoxic activity against U266B1 and RPMI 8226 multiple myeloma cell lines. Sandmeyer methodology and N-halomethylketo alkylation reaction are the two important reactions involved in the synthesis of isatin-pomalidomide hybrids (9a–9g). All the synthesized compounds (3a–3d, 4, 5, 6, and 9a–9g) were characterized by using IR, mass, 1H-NMR, and 13C-NMR spectral techniques. The efficacy of all the synthesized compounds was tested against the aforementioned cell lines by employing MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) standard protocols while using pomalidomide as a standard. The test concentrations used in the MTT assay were 1, 10, 20, 30, and 40?μM, and the period of incubation was 24?h. All the synthesized compounds were found to have moderate to greater cytotoxic activity against the aforementioned cell lines. Among them, synthesized hybrids 9f (IC50, U266B1?=?5.15?±?0.72?μM, RPMI8226?=?11.66?±?0.79?μM) and 9g (IC50, U266B1?=?2.50?±?0.37?μM, RPMI8226?=?6.70?±?0.55?μM) displayed better cytotoxic activity against both the cell lines used in the present study.

Isoindole-imide compounds, compositions, and uses thereof

The invention relates to isoindole-imide compounds and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, or mixtures of stereoisomers thereof, pharmaceutical compositions comprising these isoindole-imide compounds, and methods for reducing the level of cytokines and their precursors in mammals. In particular, the invention pertains to isoindole-imide compounds that are potent inhibitors of the production of TNF-α in mammals. The isoindole-imides described herein are useful for treating or preventing diseases or disorders in mammals, for example, cancers, such as solid tumors and blood-born tumors; heart disease, such as congestive heart failure; osteoporosis; and genetic, inflammatory; allergic; and autoimmune diseases.