202592-23-2

Usage

Uses

(+)-JQ1 Carboxylic Acid is a selective inhibitor of BET bromodomains.

Upstream product

• 916489-36-6 methyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)acetate 
• 1268524-69-1 [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-1-thia-5,7,8,9a-tetraazacyclopenta[e]azulen-6-yl]acetic acid tert-butyl ester 
• 202592-28-7 [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetic acid 
• 1268524-70-4 (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate 
• 79-04-9 chloroacetyl chloride 
• 4640-66-8 p-chlorobenzoylacetonitrile 
• 50508-66-2 (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone 
• 1268524-71-5 (-)-JQ₁ 
• 1268524-68-0 tert-butyl 2-(5-(4-chlorophenyl)-6,7-dimethyl-2-thioxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-3-yl)acetate 
• 1268524-65-7 (S)-tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate 

Relevant academic research and scientific papers

Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)-JQ1

A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)-JQ1 have been prepared. The most potent, N-[(adamantan-1-yl)methyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide, 2e, showed excellent potency with an KD=ca. 130 nm vs. BRD4(1) and a ca. 2-fold selectivity over BRD4(2) (KD=ca. 260 nm). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody-drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.

Aptamer-PROTAC Conjugates (APCs) for Tumor-Specific Targeting in Breast Cancer

Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.

METHODS AND COMPOUNDS FOR THE TREATMENT OF GENETIC DISEASE

The present disclosure relates to compounds and methods for modulating the expression of dmpk, and treating diseases and conditions in which dmpk plays an active role. The compound can be a transcription modulator molecule having a first terminus, a second terminus, and oligomeric backbone, wherein: a) the first terminus comprises a DNA-binding moiety capable of noncovalently binding to a nucleotide repeat sequence CAG or CTG; b) the second terminus comprises a protein-binding moiety binding to a regulatory molecule that modulates an expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) the oligomeric backbone comprising a linker between the first terminus and the second terminus.

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.

Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants

A parallel, one-pot assembly approach to proteolysis targeting chimeras (PROTACs) is demonstrated utilizing activated esters generatedin situ, and traceless Staudinger ligation chemistry. The method described allows for rapid structure-activity relationship studies of PROTAC linker variants. Two previously studied systems, cereblon and BRD4 degraders, are examined as test cases for the synthetic method. The two related strategies to assemble PROTAC linker variants discussed can accommodate the chromotographic separations capabilities of labs of many sizes and incorporates commercially available degrader building blocks, thereby easing synthetic entry into PROTAC chemical space.

P53 MODULATORS AND USES THEREOF

Described herein, inter alia, are p53 modulator compounds and methods of using the same. In an aspect is provided a p53 protein covalently bonded to a compound described herein. In an aspect is provided a pharmaceutical composition including a compound described herein and a pharmaceutically acceptable excipient. In an aspect is provided a method of treating cancer in a subject in need of such treatment, including administering to the subject an effective amount of a compound described herein.

Construction of an IMiD-based azide library as a kit for PROTAC research

As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment. Here we report the efficient construction of an IMiD-based azide library via a quick one-step conversion of the existing IMiD-based ami

PROTEIN DEGRADATION TARGETING COMPOUND, ANTI-TUMOR APPLICATION, INTERMEDIATE THEREOF AND USE OF INTERMEDIATE

The present disclosure relates to compounds of formula (I) and their anti-tumor uses, and their intermediates of formula (III), intermediates of formula (IV), and uses of the intermediates. The compound of formula (I) has a degrading effect on a specific target protein, which is mainly composed of three parts. The first part is a small molecule compound (SMBP, Small Molecules Binding Protein) that can bind to a protein, the second part LIN is a linker, and the three-part ULM is a ubiquitin ligand (ULM, Ubiquitin Ligase Binding Moiety), wherein SMBP is covalently bound to LIN, and LIN is covalently bound to ULM. A series of compounds designed and synthesized in the present disclosure have a wide range of pharmacological activities, including the functions of degrading specific proteins and/or inhibiting activities of specific proteins, and thus can be used in related tumor treatments.

BIFUNCTIONAL AGENTS FOR PROTEIN RECRUITMENT AND/OR DEGRADATION

The disclosure relates to new compounds, including bifunctional compounds, to be used as modulators of ubiquitination for targeted protein degradation.