Bicyclo[1.1.0]butane carboxylic amides emerged as a new class of Cys-focused electrophiles. They are considered as bioisosters of acrylamides, but their increased stability and unique reactivity can result in the development of new selective covalent binders.

We offer over 700 compounds from stock and continuously work on the synthesis of new derivatives. You can select from our growing REAL Array of currently 1 million strained bicyclobutanes and be the first to try them on your target. Synthesis of hundreds of compounds will take us a few weeks only.

New Bioisosteres of Acrylamides readily available through custom parallel synthesis and from our REAL Array

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The chemistry of bicyclo[1.1.0]butane (BCB) derivatives is vividly developing. Strained hydrocarbons (e.g., EN300-298918) were proposed by Baran as suitable candidates for selective covalent labeling of Cys-residues in polypeptides. In his study, the reactivity of bicyclo[1.1.0]butyl aryl sulfones was similar to that of acrylamides in GSH-assay. Recently, Ojida introduced BCB-amide as a covalent warhead, targeting cysteine residue. These molecules are easy to synthesize from BCB-carboxylic acid and diverse amines. Importantly, BCB-amides were tested in Ramos cells, which shows their compatibility with biological systems.

BCBs represent a novel perspective area for developing new selective covalent inhibitors. We are continuously working on the enumeration and synthesis of new strained bicyclobutane derivatives.

Examples of Bicyclobutane amides in stock

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The Kits represented here include commonly used CRBN ligands functionalized at C4 and C5 positions to avoid interference with binding affinity. The attached ligands are of variable lengths from 2 to up to 18 heavy atoms in the chain or as a part of a more rigid construction.

Apart from the standard PEG and Carba-linkers, we offer intermediates with rigid/cyclic linkers that have been successfully utilized in the design of bifunctional molecules. Linkers terminal functional groups can be easily modified through the most straightforward reactions – amide coupling or click-chemistry.

Product catalog

Key features

• Easy access, ready for delivery in plates as 50 mM and 20 mM solutions in DMSO
• Variable in length from 2 up to 18 heavy atoms

 



 

• Well-balanced composition including PEG-, Carba- and Rigid-linkers

 



 

• Variation of linker conjugation point

 



 

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Typical Formats

REAL analogs of well-known SPLAMs (SPLicing inhibitor sulfonAMides) can be readily synthesized from in-stock building blocks within 3-4 weeks.

• Indisulam REAL analogs – 210 296 molecules
• E7820 REAL analogs – 296 063 molecules
• Tasisulam REAL analogs – 17 101 molecules
• CQS REAL analogs – 1 566 molecules

Library Design

DCAF ligases have become more and more promising targets in protein degradation drug discovery. Proven efficacy and convenient chemistry make these targets attractive for developing new probes and drug candidates rapidly.

According to the structural data Indisulam and Tasisulam bind DCAF15 in an overall configuration similar to E7820, maintaining the backbone hydrogen bonds from the sulfonyl groups to DCAF15 Ala234 and Phe235 and the water-mediated hydrogen bonds. However, the methyl-to-hydrogen substitution at C4 in Indisulam limits the hydrophobic interactions with DCAF15 Val477 and Val556, while Tasisulam lacks the indole NH hydrogen bond to the backbone carbonyl of DCAF15 Phe231.

Based on the available structural data we have designed a library of potential SPLAMs from our stock Screening Collection using the following approach:

• Scaffold-based selection of potential DCAF binders using a set of known binders for DCAF15, DCAF16, DCAF11, and DCAF1.
• Generation and selection of close chemotypes/scaffolds based on diverse aryl and heteroaryl (five-membered inclusive) sulfonamides;
• Further selection based on pharmacophore modeling and docking results using available structural data of DCAF15;
• MedChem filtering according to criteria of lead/drug-likeness.

Boronics are mild and reversible covalent binders with proven efficacy and oral bioavailability. Our expertise in synthetic chemistry and high scientific interest in the field (see our publications), allowed our chemists to produce, over 5 000 boronic acid derivatives. All compounds are available for cherry-picking, and every month our experts expand our boronics library with new compounds. We have selected the most diverse 880 compounds, from Enamine stock, to compose our preplated Boronics Library. This library is available as 10 mM in DMSO and can be conveniently supplied for screening in various plates using customized plate maps. Boronics Library consists of two parts, which can be purchased separately: 400 fragments having single aromatic or aliphatic boronic groups in Boronics Fragment Library and 480 compounds having formyl boronic moiety in Formyl Boronics Library.

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Typical Formats

Bortezomib discovered as the first effective proteasome inhibitor validated the proteasome as a cancer target and revealed a novel approach in anticancer drug discovery. Further development of the next-generation proteasome inhibitor, the boronic ester prodrug Ixazomib citrate, has shown that boronic compounds can be administrated orally.

Other boron-containing drugs inhibit enzymes through formation of covalent adducts with catalytic nucleophilic residues like serine. The antifungal Tavaborole and phosphodiesterase-4 inhibitor Crisaborole, approved recently to treat psoriasis, contain benzoxaborole groups different from those reported before. More boronic compounds are in different pre-clinical and early clinical stages.

The high demand for boron-containing compounds is due to their unique electron structure. Although normally tri-coordinated, boronics readily adopts tetra-coordinated state upon exposure to nucleophiles and in such way can quickly form reversible adduct with nucleophilic residues such as serine, lysine, tyrosine, threonine, and cysteine thereby blocking the function of target proteins.

Boronic trigonal-tetragonal equilibrium, and covalent binding mode types

Enamine provides a wide range of boron compounds including boronic acids, and their more stable boronic ester analogues. In our library you could choose either aliphatic or (hetero)aromatic boronates.

Examples of pre-plated Boronic Fragments

A growing number of studies are using aromatic α-formyl boronic acids as a selective warhead targeting lysine residue. Introduction of boronic acid residue into α-position of benzaldehydes (well-known covalent warhead) dramatically enhances stability of resulting Shiff bases by formation of 5-membered complex. The covalent adducts can be reversibly cleaved, that can be an advantage in case where irreversible off-target modification is observed.

Recently research groups of Markus A. Seeliger & David R. Liu were developed subtype selective cyclophilin E reversible inhibitor with formyl boronic warhead covalently targeting lysine residue (Lys217)1. It is important that analogs with either the aldehyde or the boronic acid alone, respectively, showed reduced potency by 16-fold and 100-fold. Another example of α-carbonyl boronic warhead was developed into inhibitor of sortase A of S. aureus.

Examples of Formyl Boronates in pre-plated Covalent Screening Library