普洛药业

Full R&D Capabilities

CRO Chemistry Service

Intermediates & new modality platforms

Synthetic Route Scouting

Expertise

At APS, we have a team of scientists that bring a diverse range of experience from Medicinal to Scale-Up Chemistry. Having this expertise allows our scientists to independently assess the best synthetic routes toward intended goals with optimal efficiency.

Adaptability

Our chemistry expertise enables APS to retrosynthetically dissect products and identify key intermediates leading to the most cost-effective and efficient synthetic routes.

Methodology Optimization

Approach

APS chemists will troubleshoot multistep synthetic routes as well as individual reactions based on atom economy, step count, reagent availability, and scalability to facilitate optimal conversions toward desired products. These conversions will be characterized by both ideal time/cost effectiveness and high degrees of safety.

Technology

The APS team has access to a breadth of tools and technologies that allow screening for method optimization. These tools/technologies include:
⦁ Transition Metal Catalysis (Pd, Ni, Cu, Ru)
⦁ Microwave-Assisted Synthesis
⦁ Asymmetric Synthesis
⦁ Photoredox Catalysis
⦁ Flow-Chemistry

Scalability

Chemists at APS will translate Medicinal Chemistry routes into scalable processes that focus on optimal yield, purity, raw material cost, and operational safety.

Parallel Synthesis

Approach

At APS, our chemists will identify key intermediates with reactive handles to allow for fast Structure Activity Relationship (SAR) interrogation. More specifically, intermediates with reactive handles will provide the framework for multiple synthetic avenues (oxidations, reductions, substitutions, metal-mediated couplings, etc.) that will cover a wide range of chemical space.

Areas of Expertise

Our chemists at APS have utilized parallel synthesis for SAR interrogation in a multitude of scientific areas. These areas of focus include:
⦁ KRAS proteins for potential cancer therapies
⦁ Covalent inhibition chemistry
⦁ Chemical degraders

Capabilities

Small Molecule Library Development

Our chemistry team can effectively deliver synthetically-modified small molecule derivatives of interest with bandwidths ranging from 10 – 300 compounds per library.

Scaling Abilities

The APS chemistry team can deliver novel synthetic targets on scales both suitable for Medicinal Chemistry and Process Chemistry purposes. Our scaling abilities at APS span from mg – 200 g scale.

Analytical Services

Comprehensive Analytical Support

To ensure your desired targets are synthesized with the highest quality and purity, our facility offers comprehensive services in method development, purification, characterization, and impurity analysis.

Structure Characterization & Impurity Testing

Utilizing onsite advanced techniques, including LCMS, HPLC, and NMR, we provide reliable structural characterization and full impurity tests for customers.

Advanced Purification Systems

We handle mass-directed purification, including Chiral Purification, using HPLC/UPLC/LCMS systems from the mg to g scale, accommodating a mass-to-charge ratio of up to 3000 Da.

Peptide/Amino Acid Synthesis

Oligonucleotides, Lipids, & GalNAc

Antibody Drug Conjugates

Target Protein Degradation Intermediates

Liquid Phase Peptide Synthesis (LPPS)

Soluble anchors

At APS, use of soluble anchor tags promotes the solubility of growing peptides in organic solvents for easier handling and purification via precipitation or extraction. Furthermore, soluble anchor tags simplify reaction monitoring (NMR, HPLC, LC-MS) of and allow for peptide synthesis on an industrial scale (scalability).

Linear fragments

Chemists at APS also employ linear fragments, or previously synthesized short peptide chains (3-10 amino acids), to build longer peptides via coupling techniques. Utilizing linear fragments is beneficial as it reduces the total number of coupling steps, improves overall yield for long peptides, and minimizes side reactions/racemization.

Short cyclic peptides

Synthesis of short cyclic peptides via LPPS is imperative as they allow for enhanced stability, higher binding affinity and specificity, as well as improved membrane permeability. At APS, our team focuses on the development of short cyclic peptides for improved bioavailability.

Unnatural Amino Acid (UAA) Synthesis

Approach

Our team at APS utilizes chemical synthesis to generate non-natural amino acids. By customizing side chains or backbone structures via UAA synthesis, new functions are introduced into proteins providing new tools for advanced drug discovery and research.

Complex Peptides

Macrocyclic peptides

Macrocyclic peptides are an important area of focus within APS due to their biological benefits. These entities offer higher binding affinity and specificity, improved stability, better bioactivity, and therapeutic potential through the ability to target undruggable proteins.

Capabilities

Chemists at APS have successfully synthesized complex macrocyclic peptides from milligram to gram (0.1 g to 100 g) scales.

Solid Phase Peptide Synthesis (SPPS)

Resins

Utilization of resins in SPPS is imperative as it allows our team to improve coupling efficiency and overall peptide yield while simplifying the purification of the growing peptides. Furthermore, use of these resins will be compatible with automation techniques, making SPPS more efficient, high-throughput, and reproducible.

Alstra Synthesizer

The chemistry team within APS also has experience with Alstra Peptide Synthesizers, allowing for rapid assembly of peptides via microwave technology. Use of the Alstra Synthesizer not only accelerates the average time for each amino acid (AA) cycle (~70 min), it also allows for robust ring closure chemistry en route to cyclic peptides.

Oligonucleotide Monomer/Dimer Synthesis

Nucleotides Up to kg Scale

Chemists at APS have extensive experience when it comes to nucleotide synthesis. Nucleotide modifications include variations of nitrogenous bases as well as 2’-OH groups tailored to specific DNA and/or RNA backbones. Abilities at APS also extend to kg-scale synthesis of designated modified nucleotides

Phosphoramidites Up to kg Scale

Phosphoramidites are another class of organic compounds that are of high importance to APS. Upon synthesizing novel nucleotides as described above, generation of the corresponding amidite building blocks allows for the coupling to other unique nucleotide fragments. This enables precise syntheses of custom DNAs and RNAs (oligonucleotides) for research, diagnostic, and therapeutic purposes. Similar to nucleotides, novel phosphoramidites can be scaled to kg quantities at APS.

Dinucleotide Synthesis

Synthetic chemists at APS also blend the generation of novel nucleotides with novel phosphoramidites to make custom dinucleotides. The APS team have successfully delivered novel dinucleotides of interest in routes up to 15 synthetic steps demonstrating the team’s robustness and advanced abilities. These routes are characterized by protecting group manipulations on the nucleobase as well as the 2’-, 3’-, and 5’-positions of the nucleotide, amidite formations, and oxidations.

Synthesis of Nucleotide-Like Monomers

Robust Process – Up to kg Scale

Acyclic, nucleotide-like monomers is another area of organic chemistry where APS has extensive expertise. These nucleotide-like monomers are of importance as they are often used in medicinal chemistry, especially as antiviral agents, as they can interfere with nucleic acid synthesis. APS chemists have the ability to perform robust multistep (up to 6 steps) syntheses to access these nucleotide-like monomers in kilogram quantities.

Purification and Verification

Our capabilities at APS will ensure that your desired nucleotide-like monomer targets are synthesized with the highest quality and purity. Purification/Verification techniques include:
⦁ High purity by HPLC
⦁ 31P NMR – to diagnose between P(III) and P(V) oxidation states

PEG Lipids

Capabilities

APS chemists have the ability for extensive polyethylene glycol (PEG) derivatization. Among these derivatives include Monodisperse PEGs, Monofunctionalized PEGs, Homobifunctional PEGs, and Heterobifunctional PEGs. Various lengths of these PEG molecules (n = 1 to 48, or higher) can be synthesized at various scales upon customer request.

Monodisperse PEGs

Monodisperse PEGs are highly pure, single-molecule PEG chains with a precise, uniform length and molecular weight. The polydispersity index (PDI) of monodisperse PEGs are 1 to signify their purity/uniformity. These entities are widely used in drug delivery, bioconjugation, and surface modifications.

Monofunctionalized PEGs

PEG polymers that have a free alcohol group on one end and a different reactive group on the other (HO-PEG-R). These modalities are often used for controlled conjugation (avoid crosslinking) as well as for PEGylation of proteins, drugs, or nanoparticles.

Homobifunctional PEGs

Synthetic linkers with the structure R-PEG-R. Homobifunctional PEGs have the same reactive group at both ends and are used to connect molecules like proteins and nanoparticles to improve solubility and stability while reducing immunogenicity.

Heterobifunctional PEGs

A specialized PEG molecule with two different reactive groups at its ends (R-PEG-R’), allowing it to precisely link two distinct molecules. This approach is used for applications such as targeted drug delivery, creating antibody-drug conjugates (ADCs), and developing novel materials.

High purity and high PDI

Chemists at APS ensure that desired PEG derivatives are synthesized in high yield and with high uniformity. For Monodisperse PEGs, our aim is to synthesize the intended target in >98% yield and with a PDI of 1. Our aim for Monofunctionalized, Homobifunctional, and Heterobifunctional PEGs is to deliver these derivatives in >97% yield and with a PDI of <1.1.

GalNAc

Trivalent GalNAc

GalNAc (or N-acetylgalactosamine), an amino sugar derivative of galactose crucial for cell communication, is a key targeting ligand, especially for liver-targeted delivery. GalNAc’s high biding affinity for the asialoglycoprotein receptor (ASGPR) on liver cells enables precision therapies for various diseases, primarily through nucleic acid delivery. Here at APS, our team has the capabilities of synthesizing novel trivalent GalNAcs for liver-targeted delivery and biological diagnostics.

Ionizable Lipids

Approach

Access to ionizable lipid synthesis is imperative as it is relevant to many modern scientific trends including non-viral delivery. Ionizable lipids are prominent in novel mRNA delivery vehicles such as lipid nanoparticles (LNPs). When it comes to mRNA delivery, ionizable lipids are largely responsible for organ selection, mRNA delivery efficiency, lipid clearance, and prolonged circulation times of the LNPs. Having a strong foundation in ionizable lipid synthesis is an area of high interest at APS as many advancements are to be made in the area of non-viral delivery.

ADC Connectors

Overview

A variety of chemical modalities exist that make them effective connectors to Antibody-Drug Conjugates. These connectors are characterized by specialized, site-specific, biorthogonal transformations to activate and improve ADC activity. Our chemists at APS have extensive experience when it comes to the synthesis of the moieties described below.

Maleimides

Maleimides are versatile organic compounds that specifically react with thiol (-SH) groups such as cysteine residues in proteins. This chemoselective, biorthogonal reaction system aids in bioconjugation, materials research, and polymer science.

NHS Ester

N-Hydroxysuccinimide (NHS) esters is another organic compound that is widely used for bioconjugation. This modality specifically reacts with primary amines (-NH2) found in proteins, peptides, and small molecules.

Clickable Connectors

Click chemistry is a set of chemical reactions that are fast, reliable, high-yielding, and easy to perform. These reactions are extremely specific, often depending on the components used. At APS, our chemistry team can effectively access orthogonal clickable connectors (DBCO/Azide, TCO/Tetrazines, etc.) for tracking molecules, labeling proteins, and overall drug development.

ADC Linkers

Overview

ADC linkers are essentially chemical bridges in Antibody-Drug Conjugates that connect antibodies to potent chemotherapeutic drugs. These linkers help ensure stable delivery of these cytotoxic payloads to cancer cells that are targeted for killing. At APS, our scientists have effectively gained access to the following technologies described below.

Non-Cleavage Linker

Non-cleavable linkers within ADCs form a highly stable bond that does not decompose upon circulation within the bloodstream. Consequently, this requires the entire ADC to be internalized and degraded within the cell’s lysosomes for effective drug release.

Cleavage Linker

: Within ADCs, cleavable linkers connect the antibody to the cytotoxic payload. In these cases, however, these linkers are designed to break apart under specific conditions. Cleavable linkers may be sensitive to pH (acidic) conditions, Redox conditions, as well as exposure to certain enzymes. Our team at APS can access cleavable linkers that are specifically tailored to your needs.

Peptide

ADC peptides linkers are specialized amino acid-based/peptide linkers that connect antibodies to cytotoxic payloads making ADCs. These peptide linkers are typically 2-3 peptides in length that are very stable in circulation and have a lower risk of premature release.

Sugar

Sugar-based ADC linkers are carbohydrate-based linkers (glucose, mannose, etc.) that connect cytotoxins to antibodies. When it comes to ADCs, sugar-based linkers are of interest as they are stable in the bloodstream and are cleavable within cells once they come into contact with enzymes.

ADC Payload Collection

Overview

Antibody-Drug Conjugates (ADCs) are a unique type of cancer therapy that combines a cancer-targeting antibody, a potent chemotherapy drug (payload), and a special linker. This therapy delivers the toxic drug directly inside the cancer cells and kills them while sparing healthy tissues. At APS, we have access to a wide availability of payloads that makes ADC breakthroughs more feasible.

Microtubule Inhibitors

ACD microtubule inhibitors employ a targeted antibody to deliver a potent chemotherapeutic drug that disrupts microtubule formation, halting cell division and killing cancer cells. Our chemistry team at APS has access to various compound classes such as auristatins, tubulysin, and maytansinoids to facilitate ADC microtubule inhibitor technology.

DNA Modulation

ADC DNA modulation utilizes DNA nanostructures or DNA-damaging agents as payloads to control drug attachment, improve stability, enhance targeting, and increase the amount of potent drugs delivered to cancer cells. At APS, we specialize in synthesizing Topo I and Topo II inhibitors to enable the ADC DNA modulation technology

DNA Chain Break

Some ADCs are designed to damage DNA by inducing DNA chain breaks through cytotoxic payloads as a mechanism to kill cancer cells. Within APS, our team specializes in the synthesis of calicheamicin and derivatives thereof to cause double-strand breaks as a means for antitumor activity.

DNA Alkylation

Another class of ADCs employs a cytotoxic payload that damages DNA by alkylation, leading to cell death. Herein, chemists at APS have successfully gained accesses to the duocarmycin family – a class of natural products that bind to the minor groove of DNA and cause sequence-selective alkylation.

DNA XL

Advanced ADCs use potent DNA-damaging agents as payloads, which are designed for enhanced efficiency (or XL enhanced efficiency) in cancer therapy. ADCs with DNA XL payloads target solid tumors with better selectivity, making them more attractive alternatives relative to early ADCs. APS specializes in synthesizing pyrrolobenzodiazepine (PBD) derivatives as the XL DNA-damaging agents of interest.

E3 Ligase Inhibitors and Linkers

Overview

Our E3 ligase inhibitor and linker collection aims to explore protein degradation efficiency and boost therapeutic potency by hijacking the cell’s ubiquitin-protease system.

CRBN Ligands & Conjugates

Cereblon (CRBN) ligands and conjugates are small molecules that bind to CRBN, the substrate-receptor of the CRL4-CRBN E3 ubiquitin ligase complex. These ligands/conjugates hijack CRBN to make it degrade specific proteins. APS has 264 of these ligands and conjugates in stock (500 mg  20 g quantities), with various reactive handles on these modalities to connect to proteins of interest.

VHL Ligands & Conjugates

Von Hippel-Lindau (VHL) ligands are recruiters for the VHL E3 ubiquitin ligase complex. Their function is to bring the E3 ligase to a target protein so it can be tagged for destruction. At APS, we currently have 18 VHL ligands and conjugates in stock to connect linkers and proteins of interest with various physical properties.

PROTACs

Proteolysis Targeting Chimeras (PROTACs) are molecular entities that eliminate the protein itself by hijacking the cell’s lysosome (garbage-disposal system). More specifically, PROTACs can recruit E3 ligase and tag the protein of interest to ultimately degrade these specific proteins. At APS, we currently have access to 8 PROTACs for E3 ligase ligand binding. We are currently in the early exploration stages with this technology.

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About APS

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