Integrated Drug Discovery
Validated GPCR targets may be prioritized for high-throughput screening (HTS) at Beacon with the ultimate aim of discovering highly-characterized pharmacological tools.
Careful assay development is critical to the success of an HTS campaign. Beacon employs methods that have been honed over the years working with this receptor class to design the optimal receptor construct and test it in the ideal assay platform that will maximize chances of identifying chemical matter. During this phase rodent clones are also generated to confirm activity of hits on the rodent ortholog.
Beacon retains a 600K small molecule library to identify hits. This library has been curated over many years and is composed of both commercially-sourced and proprietary compounds (30%). Almost 100k compounds discarded from commercially-sourced libraries after PAINS/REOS/internal data filtering. This library can be employed in various assay platforms and screening modes.
Hits identified from the HTS campaign are tested in dose-response for confirmation of activity. Ideally at least two scaffolds are selected for initiation of a hit to lead campaign, preferably with activity on both the human and rodent receptor. Once these scaffolds are identified Beacon may initiate a medicinal chemistry effort to identify a pharmacological tool for proof of concept (POC) studies in the appropriate in vitro or in vivo systems.
Pharmacological Tool Identification and Testing
Medicinal Chemistry and Computational Science
Once hits have been identified from the HTS campaign focus will shift towards identifying pharmacological tools.
Beacon has significant experience in GPCR hit explosion and tool compound ID:
1. Utilizing proprietary computational methods for new compound purchase to expand initial hit set
2. Designing follow-up libraries
3. Employing computational approaches to substituent selection
4. In-House medicinal chemistry expertise to guide SAR
5. Design and implementation of receptor homology modelling to assist SAR development, particularly in identifying hits and lead optimization
Establishing Proof of Concept (POC)
Once appropriate tools are identified and synthesized, they will be used for POC studies:
1. Tool compound(s) will be tested in appropriate models (in vitro or in vivo) of disease
i. Ideally compounds will be identified from multiple scaffolds with sufficient selectivity and bioavailability
ii. Compounds with off target liabilities that might confound POC testing results are eliminated
iii. Tools will be tested against literature standards and/or competitor compounds if they exist
2. Tool compounds should demonstrate clear PK/PD in animal models consistent with their receptor activity
3. Confirmations of target engagement and activity
i. Tool compounds can be verified by testing in knock out strains, if available
ii. Evaluate blockade of agonist tools with selective antagonists, assuming availability
iii. ADME/PK confirmation of target organ exposure
4. Tool compounds can also be used to initiate efforts to identify biomarker of target engagement
5. If the tool compounds are not amenable to lead optimization we will run a parallel discovery effort to
identify series suitable for lead optimization
6. Additional biological validation to support initial POC studies is typically carried out in parallel to lead optimization efforts with new tool compounds as they become available
Ideally tool compound(s) used in proof of concept studies are appropriate leads for optimization if not Beacon scientists will continue to explore scaffolds in parallel to POC testing until a lead(s) is identified. To that end, the Beacon team has a long track record of success advancing compounds into clinical development, and is equipped to do so efficiently and expeditiously for its partners.
1. All med-chem activity is coordinated by Beacon medicinal chemists and computational scientists with synthesis conducted at our partner CROs (Chemistry CROs are target and data blinded)
2. All receptor pharmacology testing is conducted in-house using assays optimized to drive SAR and selectivity testing
3. We typically incorporate a surrogate biomarker in vivo assay into our testing scheme when possible
4. All ADME/PK activities are coordinated with our partner CROs
Lead Compound Criteria
Clear structure activity relationship
Amenability to chemical modification to rapidly improve potency, selectivity and DMPK properties
Structural novelty or some other type of patentability
Physicochemical properties consistent with drug-like or lead-like compounds
Acceptable chemical stability
Adequate potency in in-vitro screens; e.g., usually less than 100nM for typical GPCR antagonists or inverse agonists, less than 300nM for GPCR agonists
Adequate selectivity in-vitro; e.g., normally at least 10-fold versus related receptors
No insurmountable liabilities in terms of genotoxicity and hERG activity
A satisfactory DMPK profile in-vitro and/or in-vivo for the intended route of administration
P450 inhibition, IC50 > 5 uM where tested
Ideally have been used to further validate the selected target, with positive results of lead (and where appropriate, reference) compounds in a relevant model in-vivo without showing significant toxicity at the active dose and with evidence of on-target activity
The potential to provide advantages over existing and emerging therapies