Proteros biostructures and Orion Pharma agree on a long-term multi-target collaboration including the assembly of a joint novel and unique HTS small-molecule screening library with the full chemistry support of Enamine
Multi-target research partnership for drug discovery in oncology and pain
Assembly of novel high-diversity small molecule library
Library collection distinguished by novel unique design concepts based on a proprietary set of selection filters to ensure high quality and drug-likeness of individual compounds, selectively compiled from the premium chemical provider Enamine and others
Martinsried/Munich, Germany – September 06, 2023 – Proteros biostructures GmbH (“Proteros”) today announced a new collaboration with Orion Corporation (Espoo, Finland). The companies are engaging in a joint multi-target collaboration for early-stage drug discovery projects using Proteros’ “High Hanging Fruit” Discovery Platform, and now have decided to combine their expertise to assemble a unique and chemically diverse small molecule library collection. The non-exclusive agreement enables Proteros to exclusively offer access to this high-quality non-redundant HTS library to all their clients.
Under the agreement, Orion co-funded and supported the design and generation of the library containing a highly diverse collection of chemotypes for target-agnostic high throughput screening (HTS). The small molecule collection, of around 200 thousand compounds, is distinguished by its novel and unique design concept of optimized chemical diversity. Compounds are sourced primarily from the premium chemical provider Enamine a current partner of Proteros for hit follow-up chemistry services. Application of a comprehensive proprietary set of selection filters secures high quality and drug-likeness of the human-inspected individual compounds and reduces pan-assay interference compounds (PAINS) to guarantee that every compound is developable and follows desirable chemical properties. The established long-lasting collaboration with Enamine ensures high tractability and fast development of the hit compounds.
“With this novel library, we aim to enable the exploration of a highly diverse chemical space for our customers. The chemotype selection is based on stringent diversity algorithms and is ensured to be applicable to any target class,” said Lars Neumann, Director Discovery Solutions of Proteros biostructures. “This unique design allows us to offer our clients an excellent option for discovering Qualified Hits for High Hanging Fruit targets,” said Debora Konz Makino Vice President Discovery Solutions of Proteros biostructures.
“Based on our long-term experience and success of working with Proteros we are confident this agreement will boost our hit finding activities. One of the key features of
the library is also quick SAR by catalogue which will speed up hit triage significantly and allows best choice for lead optimisation programs. As we all know, quality of the hits is a key success factor for speed and success in the drug discovery program,” said Leena Otsomaa, Vice President Medicine Design of Orion Corp. “We are also very much looking forward to the collaboration for early-stage drug discovery in our key therapeutic target areas: oncology and pain indications.”
Michael Bossert, Head Strategic Alliances at Enamine, commented: “Our growing homemade screening libraries, the largest collection available in the world, constitute ideal starting points for any HTS and hit identification platform to spot possible beneficial effects against any of a large number of diseases.” He continued: “We are delighted to have been selected for this initiative as the main compound provider, and, under such collaboration, to enhance the partnership with Proteros to serve their clients each time when needed via our seamless hit follow-up chemistry services and our ADMET/DMPK capabilities.”
About Proteros biostructures GmbH
Proteros is a privately-held company with expertise in structure-based drug discovery powered by a cutting-edge discovery engine tailored to unlock even the most technically challenging disease-relevant drug targets. The company provides small molecule drug discovery services and its comprehensive enabling technology platforms, coupled with roots to Nobel Prize winning science and the Max Planck Institute of Biochemistry, have enabled prominent contributions to several lead optimization programs and clinical-stage compounds.
Proteros’ scientific rigor can accelerate overall research timelines for clients by solving the “High-hanging-fruits” of the early drug discovery and development stages and the company is consistently seen as the go-to partner for Hit to Lead Optimisation services. Proteros supports many of the world’s top 20 largest pharmaceutical companies and more than 200 pharmaceutical and biotech partners in the U.S., Europe and Japan.
Orion is a globally operating Finnish pharmaceutical company – a builder of well-being. We develop, manufacture and market human and veterinary pharmaceuticals and active pharmaceutical ingredients. We believe that health and well-being create the foundation for a good life and society. Orion has an extensive portfolio of proprietary and generic medicines and self-care products. The core therapy areas of our pharmaceutical R&D are oncology and pain. Proprietary products developed by Orion are used to treat cancer, neurological and respiratory diseases, among others. Orion's net sales in 2022 amounted to EUR 1,341 million and the company had about 3,500 employees at the end of the year. Orion's A and B shares are listed on Nasdaq Helsinki.
Recursion has predicted the protein target(s) for approximately 36 billion chemical compounds in the Enamine REAL Space, reported to be the world’s largest searchable chemical library. These advances were made possible by NVIDIA DGX Cloud supercomputing and the recent acquisition of Cyclica’s MatchMaker technology.
SALT LAKE CITY, Aug. 08, 2023 (GLOBE NEWSWIRE) -- Recursion (NASDAQ: RXRX), a leading clinical stage TechBio company decoding biology to industrialize drug discovery, today announced it has successfully screened the Enamine REAL Space chemical library using its MatchMaker technology, recently acquired from Cyclica, to predict the protein target(s) for approximately 36 billion chemical compounds. This accomplishment was made possible by several other enabling discoveries, including the predicted structures derived from the AlphaFold2 database for more than 15,000 human proteins containing more than 80,000 potential binding pockets, as well as the Enamine REAL Space, which is reported to be the world’s largest searchable chemical library comprised of approximately 36 billion make-on-demand molecules. In total, this screen digitally evaluated more than 2.8 quadrillion small molecule-target pairs.
This achievement represents a significant and exciting step toward achieving our mission of decoding biology and chemistry,” said Chris Gibson, Ph.D., Co-Founder and CEO of Recursion. “Until this point, the groundbreaking progress across biology and chemistry that enabled this moment – namely, AlphaFold, the Enamine virtual chemical library and the rapid advancement of large-scale compute and new machine learning approaches – have largely lived in isolation of one another or have been bridged at relatively small scales. Leveraging Recursion’s machine learning and computational expertise and NVIDIA’s technology, we have layered these advances together to predict how each of the molecules in this vast chemical universe may interact with the protein universe.
The company generated this massive new data layer of predicted interactions in less than 90 days after closing the acquisition of Cyclica and in under 30 days since initiating the collaboration with NVIDIA.
MatchMaker uses machine learning to assess whether a small molecule is compatible with a specific protein binding pocket, providing a solution that is significantly less computationally intensive and much more scalable than traditional docking and physics-based interaction simulations. Similar to Recursion’s phenomics platform, the scalability of MatchMaker enables a “high-dimensional” view of biochemistry: activity is predicted not just for a single target, but for many at the same time. This enables three core advantages: First, this predicted data layer can be used to determine which wet-lab experiments should be executed to advance programs faster across a wide range of targets and chemical space. Second, this predicted data layer can be used as part of Recursion’s multi-modal dataset to better understand biological activity across programs quickly and at scale. Finally, this approach can pre-screen for more computationally expensive precision modeling techniques implemented by Recursion’s computational and digital chemistry teams, to more efficiently advance programs.
We are excited to collaborate with Recursion to explore the chemical space and support our mission to accelerate drug discovery,” said Andrey Tolmachev, Ph.D., Founder and Owner of Enamine. He continued: “This achievement in the 36 Billion REAL Space is just a start of our journey. The chemical knowledge accumulated at Enamine over its 35-years history allows us to explore trillions of relationships without compromising the high success rate of synthesis. We believe the predictions made by Recursion can help us prioritize parts of the chemical universe and provide an opportunity to develop focused chemical spaces and novel compounds around discovered hits quickly.
Much of the initial testing and infrastructure development for the project was completed using BioHive-1, Recursion’s in-house supercomputer, an NVIDIA DGX SuperPOD, which is ranked among the top 125 most powerful supercomputers in the world across any industry by TOP500 as of June 2023. The final analysis was made possible by NVIDIA’s DGX Cloud, an advanced AI-training-as-a-service solution to which Recursion gained access following its recently announced collaboration with NVIDIA. Recursion worked with urgency to make this effort happen in a short period of time.
Bringing together powerful data, AI and data-center scale compute, Recursion’s MatchMaker running on NVIDIA DGX Cloud essentially created a time machine for the company’s drug discovery program and sets a new bar for the industry,” said Kimberly Powell, Vice President of Healthcare at NVIDIA. “Within one week, the Recursion team was able to achieve what would have otherwise taken 100,000 years to compute with physics-based methods — setting the stage for a wet-lab, dry-lab flywheel to better predict drug-target interactions and increase a drug’s probability of success in the clinic.
Recursion plans to leverage this new database of predictions to industrialize its chemistry operations across its pipeline and in service to its partners, enabling significantly greater efficiency in its medicinal chemistry cycles. Further, Recursion plans to continue improving and expanding the number and type of chemical properties and interactions it can predict using in-house tools, tools acquired through the acquisition of Cyclica, and tools being developed by Valence Labs, the semi-autonomous research hub powered by Recursion and formed through the acquisition of Valence Discovery.
Namiki and Enamine have collaborated for over 20 years, and for the most part of this time,
Namiki was an exclusive distributor of all Enamine products and services. Namiki is an
excellent partner providing services on the highest level under any circumstances.
Promising and more stable isosteres of acrylamides
724 compounds in stock 320 pre-plated compounds
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
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
Ready-to-use sets to support your discoveries
We at Enamine are constantly working on synthesizing new molecules and elaborating new synthetic approaches to facilitate access to the most demanded chemistry and intermediates for the Drug Discovery Community. We carefully designed and synthesized a series of E3 binders with attached linkers of different lengths and natures to support Degrader Research and Development. Our primary focus has been the derivatization of Cereblon (CRBN) binders since they are most frequently used in constructing PROTAC molecules.
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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
Product name
Description
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Product name
CRBN Amine Kit-1
Amine-1-96
Description
Thalidomide-based ligands derivatized with most comprehensive and diverse linkers of variable length from 2 to 18 heavy atoms in a chain with terminal amine functional group
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Product name
CRBN Amine Kit-2
Amine-2-35
Description
Uracyl-based Cereblon ligands with linear PEG- and Carba-linkers with terminal amine group able for modification
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Product name
CRBN Azide Kit-1
Azide-1-28
Description
Thalidomide-based ligands with linear PEG- and Carba-linkers with terminal azide function for Click chemistry
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Product name
CRBN Acid Kit-1
Acid-1-40
Description
Thalidomide-scaffold derivatized with diverse linkers of variable length from 2 to 18 heavy atoms in a chain with terminal acid functional group
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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
Designed to target DCAF family of E3 ligases
5 440 pre-plated compounds
For a long time, Indisulam and a few other clinically tested aryl sulfonamides such as Tasisulam and chloroquinoxaline sulfonamide (CQS) remained compounds with pronounced selective in vitro anticancer activity and unclear action mechanisms. Recent extensive investigations in cancer genome sequencing together with X-Ray crystallography and cryo-EM showed that these compounds act as a “molecular glue” to induce degradation of RBM39 via complex formation and recruiting CUL-4-DCAF15 E3 ligase. This insight provided structural and mechanistic data that significantly extended our understanding of their mode of action. Further research in this area reveals covalent binders of other members of DCAF family proteins, such as DCAF1, DCAF11, and DCAF16.
Recent structural data and reported DCAF binders allowed us to design a dedicated library of compounds with the potential to act as molecular glues. The library is now available in a pre-plated format and can be quickly delivered in any convenient for your project format.
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.
Docking results
Examples of SPLAM analogues
Over 5000 boron-containing compounds in stock
880 pre-plated compounds
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.
384-well plates Greiner 781280, 320 compounds per plate, first two and last two columns empty
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Catalog No.
Boronics Fragment Library BAF-400-25-X-100
Compounds
400 5 plates
Amount
25 µL of 100 mM DMSO solutions
Plates and formats
96-well plates, 2D-barcoded Matrix microtubes #3734, 1 and 12 columns empty, 80 cmpds per plate
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Catalog No.
Boronics Fragment Library BAF-400
Compounds
400
Amount
Custom
Plates and formats
Any custom format
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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
3 953 compounds in stock and over 1.1 million in REAL
1 760 pre-plated compounds
Sulfonyl fluorides are becoming increasingly popular in covalent probe discovery and are often used as tool compounds in chemical biology. Their high stability and low reactivity made them promising in modern drug discovery. Sulfonyl fluorides are known to react with multiple nucleophilic amino acid residues including Tyr, Lys, His, Arg, Ser and Thr. That is especially important due to the much higher abundance of Ser and Lys in proteins over Cys (on average about 9% and 6% vs 2%).
There is a significant difference in reactivity between fluoro sulfonates, sulfamoyl fluorides, and alkyl aryl/hetaryl sulfonyl fluorides, which enables the design of selective covalent binders. For example, less reactive fluoro sulfonates have been reported to react better with Tyr phenolic hydroxy groups than sulfonyl fluorides and sulfamoyl fluorides.
A recently published study by the research group at GSK on hydrolytic stability and reactivity of various sulfonyl fluorides, reveals interesting findings and a way to profile sulfonyl fluorides. Several substituted benzene sulfonyl fluoride scaffolds have been reported to possess balanced reactivity due to enough stability to hydrolysis and moderate activity toward nucleophiles.
Currently we offer over 100 compounds from stock and synthesis of new derivatives are in progress.
REAL Sulfonyl Fluorides
Over 701k REAL Sulfonyl fluorides, including aryl, hetaryl and alkyl sulfonyl fluorides
