Cambridge Healthtech Instituteの第2回年次会議
bRo5: Macrocyclics, Degraders & More
2023年4月12 - 13日
創薬化学者にとっての新たなフロンティアは、低分子よりも困難な細胞内標的に対抗できる、標的タンパク質分解誘導（TPD）向けの大環状分子、拘束性ペプチド、二官能性分解誘導剤などの大きな分子を設計することです。しかし、このような化合物は、経口バイオアベイラビリティ、溶解性、細胞透過性といった低分子の有利な薬物特性を維持することが困難です。すなわち、リピンスキーのルールオブファイブ（Ro5）を超えることが、共通の課題となります。Cambridge Healthtech Instituteの第2回年次会議「ルールオブファイブ（Ro5）を超えて」では、創薬化学者、計算化学者、合成化学者とともに、成功事例について議論し、これらの新しい「大きな低分子」薬剤モダリティに取り組むための戦略について話し合います。
Registration Open12:00 pm
Dessert Break in the Exhibit Hall with Poster Viewing12:45 pm
Welcome Remarks1:30 pm
Macrocyclics Traversing the Membrane
Gaurav Bhardwaj, PhD, Assistant Professor, Medicinal Chemistry, University of Washington
Developing macrocyclic binders against intracellular proteins and protein-protein interfaces remains a challenge with current methods and scaffolds. We recently developed computational methods to design peptides with enhanced membrane permeability and oral bioavailability. We are further integrating our computational methods with high-throughput peptide synthesis to design peptide binders for antibiotic, antiviral, and other therapeutic applications. Overall, these methods present avenues for binding intracellular targets currently considered "undruggable" or "difficult to drug."
Heterocycles, Privileged Scaffolds, and Permeable Macrocyclics
Andrei K. Yudin, PhD, Professor, Chemistry, University of Toronto
To design passively membrane permeable bioactive macrocycles, chemists have resorted to N-methylated amino acids and/or unnatural amino acids. We replaced select amino acid residues by azole heterocycles in a stepwise manner, which vastly improved the lipophilicity and PAMPA permeability of macrocycles. NMR analysis and molecular dynamics demonstrated permeability did not linearly increase with the addition of heterocycles. This study paves a way to discover privileged macrocyclic scaffolds for drug discovery.
Sponsored Presentation (Opportunity Available)2:40 pm
Refreshment Break in the Exhibit Hall with Poster Viewing3:10 pm
Non-Peptidic Macrocycles for Molecular Glues
Thomas Kodadek, PhD, Professor, Department of Chemistry, University of Florida, Scripps Biomedical Research
This lecture will discuss the development of efficient methods for the solid phase synthesis and on-resin screening of DNA-encoded libraries (DELs) of non-peptidic macrocycles. Because the macrocycles contain few amide N-H bonds, they display good intrinsic cell permeability. Stringent quality control measures have been established to ensure that almost all of the molecules in the library are indeed macrocyclic. Novel FACS-based screening methods to mine these libraries for highly selective target protein ligands, including molecular glue candidates, will be highlighted.
A New Technology to Make Cell-Permeable and/or Oral Cyclic Peptide Drugs
Edward Will, PhD Candidate, LPPT, Professor Christian Heinis, EPFL
I will describe our method for synthesizing and screening ten-thousands of macrocyclic compounds at a picomole scale (S. Habeshian et al., Nat Commun. 13, 3823, 2022). Our new platform yields small cyclic peptides (< 700 Da) that have physicochemical properties suited to enter cells or for oral delivery.
In-Person Group Discussions5:00 pm
Making Large Molecules More Palatable
Close of Day5:45 pm
Dinner Short Courses*6:15 pm
*Premium Pricing or separate registration required. See Short Courses page for details.
Registration Open7:15 am
Diversity in Chemistry Breakfast Discussion (Sponsorship Opportunity Available)7:45 am
Diversity in Chemistry beyond Molecules: Gender and More
Michelle Arkin, PhD, Chair and Distinguished Professor, Pharmaceutical Chemistry & Director, Small Molecule Discovery Center, University of California, San Francisco
We encourage all to attend this moderated, audience-interactive discussion session. When it comes to increasing diversity among scientists, there continues to be a drop-off as one moves higher in leadership. Where do systemic challenges remain, what is your experience, and how can we continue to equalize the system?
Topics may include below, but will be guided by audience input:
- Where does the 'drop-off' of women in the chemistry career progression pipeline occur and why?
- How did the pandemic and other sea changes in the past three years bring us closer to or further from equality?
- What issues arose that you thought were solved?
- Diversity in life paths should include us all - how are men and nonbinary scientists being included?
- Intersectionality and equality - what is the experience of women of color, first-generation women scientists, and others?
PLENARY KEYNOTE SESSION
Plenary Keynote Introduction (Sponsorship Opportunity Available)8:35 am
Reflections on a Career as a Medicinal Chemist in Drug Discovery
Nicholas A. Meanwell, PhD, Vice President (recently retired), Small Molecule Drug Discovery, Bristol Myers Squibb Co.
A successful drug candidate depends on many factors: creativity of scientists involved, effective collaboration and commitment by the team, and the quality of the compound advanced. I reflect on a 40-year career pursuing the discovery of drug candidates designed to address unmet medical need in the cardiovascular, CNS, and viral diseases therapeutic areas and share undervalued strategies and other synthetic chemistry approaches for overcoming specific medicinal chemistry challenges.
Coffee Break in the Exhibit Hall with Poster Viewing9:30 am
The Surprising Abundance of Passive Permeability in Large Macrocyclic Peptides beyond the World of Natural Products
Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz
The virtual chemical space that includes synthetically accessible macrocyclic peptides (MCPs) in the 1000-MW range is astronomical. While the proportion of those compounds that are cell permeable may be low, because the space is so vast, the total number of permeable MCPs above 1000 MW is high. I will describe high-throughput synthetic and analytical tools for the discovery of large, passively permeable MCP scaffolds toward ligands against challenging intracellular targets.
An Integrated Platform for the Structure-Based Design of Orally Bioavailable Macrocycle Therapeutics
Andrew T. Bockus, PhD, Associate Director, Chemistry, Circle Pharma, Inc.
Circle Pharma has established an indication-agnostic peptide macrocycle discovery platform that combines structure-based design, physics-based permeability prediction, and semi-automated synthesis. The integrated workflow enables the rational exploration of vast chemical space to identify potent and permeable macrocycles in rapid iterative design cycles. This platform has produced orally bioavailable macrocyclic inhibitors of intracellular protein-protein interactions that demonstrate in vivo efficacy in mouse xenograft tumor models.
Sponsored Presentation (Opportunity Available)11:25 am
Discovery and Development of Rusfertide (PTG-300), a Hepcidin Mimetic for the Treatment of Polycythemia Vera (PV)
Ashok Bhandari, PhD, Senior Vice President, Discovery Chemistry & Process Research, Protagonist Therapeutics, Inc.
Protagonist utilized its peptide technology platform for the de novo drug discovery of first and best-in-class drugs. The peptide technology platform produced novel peptides both oral and injectable clinical assets that include and not limited to rusfertide, PN-943, and PN-235. Will present the discovery and development of rusfertide (PTG-300), an hepcidin mimetic for the Treatment of Polycythemia Vera (PV).
FEATURED PRESENTATION: Oral Peptides: Theory and Practice
Lauren G. Monovich, PhD, Director, Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc.
Traditionally, permeable macrocyclic peptides have been identified by discrete synthesis and careful side-chain variation of privileged, natural product scaffolds. Recent advances in the principles governing passive permeability were applied to the prospective design of macrocyclic peptides with oral bioavailability. Herein, we present an expanded set of permeability-biased scaffolds and a case study describing the design of a passively permeable, orally available scaffold from a 13-mer PCSK9 ligand.
Transition to Lunch12:40 pm
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own12:50 pm
Refreshment Break in the Exhibit Hall with Poster Awards Announced1:20 pm
Poster Award (Sponsorship Opportunity Available)
ENCODED LIBRARIES FOR ORAL MACROCYCLICS
Discovery and Optimization of an Oral PCSK9 Macrocyclic Inhibitor from mRNA Display Screening
Thomas J Tucker, Principal Scientist, Medicinal Chemistry, Merck & Co Inc
This talk will highlight the discovery efforts from mRNA display screening hits to a tricyclic peptide PCSK9 inhibitor drug candidate, which demonstrated its pharmacodynamic effects similar to the FDA-approved, parenterally dosed anti-PCSK9 mAb, with the advantage of oral administration using lipidic dosing vehicle Labrasol.
Improved DNA-Encoded Libraries for Macrocyclic Peptides
Libraries and Display Selection for Macrocycles with Better Membrane Permeability
Networking Refreshment Break3:35 pm
MAKING DRUG-LIKE DEGRADERS
Bifunctional Degradation Activating Compounds - Overcoming ADME Challenges
Prasoon Chaturvedi, PhD, Vice President & Head, DMPK, C4 Therapeutics, Inc.
Targeted Protein Degradation has the potential to transform the treatment of disease. C4T’s TORPEDO platform enables the design of potent, selective, and orally available targeted protein degraders including monofunctional or MonoDAC degraders and heterobifunctional or BiDAC degraders and has delivered a robust pipeline of preclinical candidates. The presentation will discuss in vitro and in vivo strategies and challenges in the context of degrader drug discovery. As a case study, preclinical ADME properties of CFT8634, a potent, selective, and orally available BiDAC degrader of BRD9 for the treatment of SMARCB1-perturbed cancers will be discussed.
Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation
Jennifer D. Venable, PhD, Senior Scientific Director, Discovery Chemistry, Janssen Pharmaceuticals, Inc.
A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach focusing on linker effects. A large number of linker analogs, with varying length, polarity, and rigidity, were rapidly prepared and, without chromatographic purification, characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity.
In cellulo PROTAC Assembly from Reversibly Interacting Components
Thomas Kodadek, PhD, Professor, Department of Chemistry, University of Florida, Scripps Biomedical Research
A significant drawback of PROTACs is their large size, which will likely limit bioavailability, especially to the CNS and in solid tumors. Here we show that rapidly reversible bio orthogonal reactions can be employed to assemble active PROTACs inside of cells from their component target protein and E3 Ub ligase ligands. These much smaller pieces may exhibit superior bioavailability and in vivo efficacy for some applications.
Discovery of FHD-609: A Potent and Selective Heterobifunctional Degrader of BRD9
Matthew Netherton, PhD, Senior Director, Medicinal Chemistry, Foghorn Therapeutics
Synovial sarcoma is a rare, often aggressive malignancy with limited therapeutic options. In preclinical studies, FHD-609 has been shown to selectively degrade bromodomain-containing protein 9 (BRD9), taking advantage of a synthetic lethal relationship with the SS18-SSX translocation. The discovery and optimization of this first-in-class clinical compound will be described.
Close of Conference5:55 pm