Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.

/pdf/induced-protein-degradation-an-emerging-drug-discovery-4jbmzgyyxh.pdf

Induced protein degradation: an emerging drug discovery paradigm

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

Structural basis of PROTAC cooperative recognition for selective protein degradation.

Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.

Kinase inhibitors: the road ahead

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

https://www.pnas.org/content/pnas/113/26/7124.full.pdf

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.

본 발명은 특정 신규한 화합물에 관한 것이다. 특히, 본 발명은 하기 화학식 (I)의 화합물 및 이의 염에 관한 것이다. 본 발명의 화합물은 키나제 활성, 특히 PI3-키나제 활성의 억제제이다.

키나제 활성의 억제제로서의 화학적 화합물

The development of irreversible ITK inhibitors as a potential new treatment for severe asthma

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase

Covalent inhibition is a powerful strategy to develop potent and selective small molecule kinase inhibitors. Targeting the conserved catalytic lysine is an attractive method for selective kinase inactivation. We have developed novel, selective inhibitors of phosphoinositide 3-kinase δ (PI3Kδ) which acylate the catalytic lysine, Lys779, using activated esters as the reactive electrophiles. The acylating agents were prepared by adding the activated ester motif to a known selective dihydroisobenzofuran PI3Kδ inhibitor. Three esters were designed, including an acetate ester which was the smallest lysine modification evaluated in this work. Covalent binding to the enzyme was characterized by intact protein mass spectrometry of the PI3Kδ-ester adducts. An enzymatic digest coupled with tandem mass spectrometry identified Lys779 as the covalent binding site, and a biochemical activity assay confirmed that PI3Kδ inhibition was a direct result of covalent lysine acylation. These results indicate that a simple chemical modification such as lysine acetylation is sufficient to inhibit kinase activity. The selectivity of the compounds was evaluated against lipid kinases in cell lysates using a chemoproteomic binding assay. Due to the conserved nature of the catalytic lysine across the kinome, we believe the covalent inhibition strategy presented here could be applicable to a broad range of clinically relevant targets.

Acetylation of the Catalytic Lysine Inhibits Kinase Activity in PI3Kδ.

α-ketoglutarate (αKG) is a central metabolic node with far-reaching influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyloxalylglycine (DMOG) have been broadly used as tool compounds both in vitro and in vivo to study αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, a substrate of the monocarboxylate transporter MCT2. The expression level of MCT2 determines the intracellular concentration of NOG, and, as such, influences the molecular targets NOG engages with. Here we show that DMOG and MOG are highly unstable also in mouse blood. We therefore designed and characterised a series of MOG analogues with two aims: to improve pharmacokinetic properties, and to explore the pharmacophore of MCT2, a relatively understudied member of the SLC16 family. We report MOG analogues that maintain MCT2-dependent uptake, including NOG-generating compounds that replicate the metabolic effects of MOG in a concentration-dependent manner. One such analogue, IPOG, shows significantly increased blood stability, and an improved overall pharmacokinetic profile, leading to increased NOG accumulation in MCT2-expressing tumours versus isogenic controls.

https://www.biorxiv.org/content/biorxiv/early/2021/03/15/2021.03.15.433711.full.pdf

Sebastien Andre Campos

Papers

키나제 활성의 억제제로서의 화학적 화합물

The development of irreversible ITK inhibitors as a potential new treatment for severe asthma

Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase

Acetylation of the Catalytic Lysine Inhibits Kinase Activity in PI3Kδ.

Development of novel MOG analogues with increased stability to explore MCT2 and α-ketoglutarate biology in vivo