Q&A: Novel Macrocyclic Drugs for cancer Treatment – Exploring “beyond rule-of-five (bRo5)” chemical space

Dr. Spandan Chennamadhavuni, Emory University

Q: Increasing the Mw what is happening with this compound’s solubility?
A: Solubility of the drug candidate depends on many physicochemical properties such as Mol. Weight, cLogP, Polar surface area, no. of hydrogen bond donors and hydrogen bond acceptors etc. Therefore, it is possible to make drug molecule more soluble even if the molecular weight is high (major example in the literature is Cyclosporine).

Q: Can macrocycles be designed to induce PPI rather than to inhibit? Are there any successful examples?
A: We could imagine bifunctional small molecules that could interact with two different proteins could be used to bring two proteins together. (Stabilize protein-protein interactions). Typically due to very nature of macrocycles (occupying multiple extended binding sites), they are typically used for inhibiting protein-protein interactions. There are few examples of natural product based macrocycles that were used to induce PPIs (For example Swinolide A, Rhizopodin and Lobophorolide etc.) Please see review article “Expert opinion on drug discovery, 2017, vol. 12, no. 9, 925–940” for more details. 

Q: How did you select the binding pocket? Because the peptide binds to the large surface area then what could be the rationale to select that binding pocket?
A: There was no co-crystal structure of macrocycle bound to our PPI target. Our crystallography collaborators tried to get X-ray crystals for number of years. We opted to use FTMap, a computational method to find the druggable “hot spot” region on the protein surface. Our macrocycle design strategy was to have conformationally either flexible or rigid carbocycles with small substituents in the periphery. Therefore. The idea was those small substituents would occupy the binding hot spots and carbocycle would keep the small substituents in place. Our hypothesis was that we need to occupy those shallow binding pockets on the protein surface to cause PPI inhibition.

About FTMap In brief, Binding hot spots, protein sites with high-binding affinity, can be identified using X-ray crystallography or NMR by screening libraries of small organic molecules that tend to cluster at such regions.

FTMAP, a direct computational analog of the experimental screening approaches, globally samples the surface of a target protein using small organic molecules as probes, finds favorable positions, clusters the conformations and ranks the clusters on the basis of the average energy. The regions that bind several probe clusters predict the “binding hot spots”, in good agreement with experimental results. Small molecules discovered by fragment-based approaches to drug design also bind at the hot spot regions. To identify such molecules and their most likely bound positions, we extend the functionality of FTMAP (http://ftmap.bu.edu/param) to accept any small molecule as an additional probe. In its updated form, FTMAP identifies the hot spots based on a standard set of probes, and for each additional probe shows representative structures of nearby low energy clusters. This approach helps to predict bound poses of the user-selected molecules, detects if a compound is not likely to bind in the hot spot region, and provides input for the design of larger ligands.

Q: How do you explain oral bioavailability of macrocycles despites their physio-chemical properties (high MW, high TPSA, ClogP)?
A: Please refer to our Nature Chemical Biology article (Nat Chem Biol. 2014 Sep; 10 (9):723-31. doi: 10.1038/nchembio.1584.) The factors that effects oral bioavailability of macrocycles
Macrocycles have a number of inherent advantages that improve their prospects for achieving oral bioavailability, even when their physical properties lie outside the traditional Rule-of-5 chemistry space. Macrocycles could adopt three-dimensional conformations that overcome barriers to permeability. If we take the example of cyclosporine, it is orally available due to “Intramolecular Hydrogen Bonding” capability of the molecule that would allow the molecule to permeate through the cell despite of its high molecular weight.

Q: Is virtual conformer generation for macrocycles more challenging than regular compounds? Are there steps that require more care or treated differently?
A: Synthesis of macrocyclic library takes huge resources thus generating virtual combinatorial library of macrocycles is definitely a proper approach. We do need to filter virtual macrocycle library through our physicochemical properties filter to find “drug-like” macrocycles. At this stage, we generated ensemble of conformations for each macrocycles. It is not challenging as it is done in silico. We need to be careful in setting the energy parameters correct to get reasonable number of conformations. For example, if the macrocycles has too many rotatable bonds, then we would get hundreds of conformations for each molecule. Nevertheless, we choose 3-4 distinct conformations per macrocycle to use them in our docking studies.

Q: Are there some macrocyclic libraries publicly available?
A: None of the macrocyclic libraries is publicly available. However, we routinely collaborate with academic and Industry all around the world to screen our compounds. If you want to screen our proprietary macrocyclic library or any other compounds from our library in your HTS assay, you need to fill out this questionnaire: https://www.bu.edu/cmd/contact-us/screen/
We will review and arrange a time to speak in more detail about a potential collaboration and initiate preparation of our material transfer agreement. For further details, please reach out to Prof. Lauren Brown and Prof. John Porco at CMD.

Q: All the macrocyclic compounds you have synthesized (or shown) contain a trans-double bond. Did you also make the corresponding cis-compounds?
A: We did all synthetically feasible structural modifications to our macrocycles including isomerizing trans-double bond to cis to facilitate macrocylization via Thorpe–Ingold effect. We also did N-methylation, further functionalization of macrocycles to synthesize structurally diverse and complex macrocycles etc. 

Q: Have you considered using thioacetones to incorporate sulfur atom into the cycles?
A: We certainly considered thiolactones. The results from that study would be published in due course. There are certain stability issues associated with thioesters in a macrocycles that would be discussed in the due course. 

Q: What is the solubility of these macrocyclic compounds overall in general?
A: Our macrocyclic library has reasonable solubility. We routinely send out compounds in the 96 well plate for HTS assays. We did not see any difficulties in conducting assays thus far. 

Q: APE1 inhibitors seem to have µM affinities: would it be sufficient to effectively inhibit the PPI in cells, in animal models and ultimately in human patients?
A: As you could imagine, getting micro molar affinity for PPI targets (traditionally undruggable targets”) is itself is fundamental a proof of concept discovery that shows we could use macrocycles and/or bRo5 compounds for inhibiting PPI targets. We needed to make lot more progress in designing cell permeable, orally available macrocyclic drugs that would show efficacy in animals and humans. We are certainly making big strides in that direction. 

Q: Does degree of conformational rigidity of the macrocycle affect cell growth inhibition?
A: Yes, Conformational flexibility/rigidity has lot of influence on its cell permeability. Whether you would want to synthesize a conformationally restrained macrocycle or flexible macrocycle that would depends on the target of our interest. 

Q: How to address the macrocycle synthetic limitation for increasing scaffold diversity and rapid generation of analogues in a medicinal chemistry context?
A: It is a very difficult question to answer. Our goal is to discover and develop methods for synthesizing structurally complex and diverse macrocycles in a straightforward combinatorial fashion to explore diverse chemical space, carbocycles size, stereochemically diversity etc. It is the challenge that every medicinal chemist face, while doing any synthesis project. 

Q: Do you foresee the feasible strategies for macrocycle drug scale-up challenges?
A: We certainly anticipate issues in scaling-up macrocycle synthesis. We are trying to address now. There are several pharmaceutical drugs that are currently in the market that went through regular process development process and bulk scale production of those macrocycles is already established. Some macrocycle industrial production require semi-synthesis from a natural source. Nevertheless, I still feel that process chemistry of bRo5 compounds still in its infancy. 

Q: How to optimize the macrocyclic linker for drug-likeness properties (permeability, solubility, metabolic) without detriment to activity?
A: I think, the best approach is do regular structure based rational design of macrocycles for the biological target of interest to find the “Hit”. We could think of incorporating drug-like properties during hit to lead optimization step. I do not think there is a set protocol for optimizing rationally. Its try, fail, learn and repeat method for the time being. 

Q: What is the highest yield ring cyclization method(s)? I think you said the mactrolactamization had a yield of 19%.
A: Sorry for the mispronunciation. Our best yields are 99% not 19%. 

Q: What is optimal macrocycle size for achieving oral bioavailability? Comparing calculated physicochemical properties for the macrocyclic drugs with their route of administration reveals that orally administered macrocycles are smaller in size and more lipophilic than parenteral macrocycles, as further indicated by their lower polar surface area (PSA) and fewer hydrogen bond donors (HBDs)
A: According to our study, we think 12 to 15 membered macrocycles would be optimal. However, it also depends on the PPI target that we are working with. 

Q: What field do you use for the structural analysis? R-field? Born Solvation etc.?
A: We used standard docking methods using Schrodinger suite and/or autodock vina for our docking studies. We used OPLS force field and Born solvation settings. As I was involved in virtual library generation of millions of compounds, our collaborators did the docking studies. I hope this answers your question. 

Q: How stable are the macrocycles metabolically? Are the cycles easily breakable?
A: We are still working on finding the metabolic stability and cell permeability of the synthetic macrocycles. The results would be published in due course. These macrocycles are certainly chemical stable and not breakable. We routinely do QC on the samples before sending them out for HTS and we did not observe any noticeable degradation in most of the macrocycles over time.

Q: What is the route of administration for the 80-100 FDA approved drugs that are bRo5?
A: Most of the non-oral macrocycles and bRo5 compounds are administrated parenterally (route other than digestive tract) administration: subcutaneous (SC/SQ), intraperitoneal (IP), intravenous (IV), intradermal (ID), and intramuscular (IM). It depends on the disease it is getting used for. 

Q: Can you please talk about the use of DNA Encoded Libraries (DELs) to find novel small molecule molecular glues that do not follow the rule of 5? I.e. what are empirical, non-rational methods to discover small molecules that do not appear drug like?
A: This is such a broad question that would be very hard to answer. Please look at the technology developed at Ensemble Therapeutics (https://www.ensembletx.com/) and their publications. They develop DELs of macrocycles. If you do not want to use rational drug design to find the bRo5 compounds, then only option would to do high-throughput screening of several thousands of bRo5 compounds that are already available through various sources. However, chances of finding something interesting would be very slim. 

Q: Is Macugen (Pegaptanib) included in the 100 list of FDA approved drugs, which do not follow the rule of five? Alternatively, any other RNA drug?
A: Please find the poster for Beyond Rule of Five (bRo5) Drugs.
https://njardarson.lab.arizona.edu/content/top-pharmaceuticals-poster

David Preston
David Preston

Chairman

David Preston has had 38 years of healthcare experience with publicky Traded and Private companies in the fields of Phammaceuticals, Animal Health and Biotechnology as a Board Member. The last 30 years of his xperience has been in China, Taiwan and Hong Kong building successful igh growth businesses. David Has been Chaiman and CEO for Greater China for Sanofi and Boehringer – Ingelheim as well as the Janssen Corporation since 1991 in China. During this time he build high Growth ousinesses in China through diversified strategies in Innovative Pharmaceuticals. branded Generics. Biotechnology. and Animal Healthcare.

Key highlights in this period indluded building of the first Westem Multinational Biotechnoloqy C.M.O. facility as well as obtaining the first Test CM.OJ MAHI license. Establishment of a number of High tech Vaccine Plants, and R and D facilities in in the field of Animal Health. Signing and development of numerous JV’s as well as Wholly owned Subsidiaries. Mergers and Acquisitions across Phamaceutical’s. Animal Health. and Biotechnology industries

David’s achievement’s in the Healthcare industry and it Growth and development in China is widely recognized By the Chinese Govemnment and the City of Shanghai In 2013 he was awarded the Silver Magnolia ollowed in 2015 the Gold Magnolia award. This was then followed by being awarded in 2017 the Honorary Citizen of Shanghai by 40th People’s Municipal Congress of Shanghai. David Holds a Business Science Degree

This will close in 0 seconds

Filippo
Filippo de Vecchi

Director, Advent Partner

Filippo de Vecchi joined Advent in February 2000. He started in the Advent São Paulo office, then moved to Milan in 2002, in 2012 set up the Advent office in Shanghai and in 2016 set up the Hong Kong office. Before joining Advent, he was a senior consultant with Value Partners, in São Paulo and Milan, focusing on strategy and organization in the automotive, energy, cable and media sectors. He began his career at Wasserstein Perella & Co., working as an analyst in the Mergers and Acquisitions department in London and New York. Filippo holds an undergraduate degree cum laude in Economics, with a major in Business Administration, from the LUISS University and an MBA from Columbia Business School, where he currently serves as a member of the Board of Overseers.

This will close in 0 seconds

Andrew Li
Andrew Li

Director, Advent Partner

Andrew Li joined Advent in 2012. He previously worked at Warburg Pincus, HSBC PE, Solera Capital and Credit Suisse where he focused on the retail and consumer, healthcare, industrial, and energy sectors. Andrew has worked in finance and private equity throughout the U.S. and China since 1999. Andrew holds a BA from Middlebury College and an MBA from Harvard Business School.    

This will close in 0 seconds

Michael Miltenberger
Michael Miltenberger

Director, Advent Partner

Michael Miltenberger  joined Advent in 2011 as an associate on the healthcare team. Following business school, he rejoined Advent’s Boston office, focusing on healthcare investments. Prior to Advent, Michael was a consultant at McKinsey & Company in their Washington DC office, serving a range of healthcare and private equity clients. Michael earned a BA, cum laude, from Harvard College and an MBA from Harvard Business School, graduating with High Distinction as a Baker Scholar and a Harvey Fellow.

This will close in 0 seconds

Masood Tayebi
Masood Tayebi, PhD

Director, Operating Partner

Dr. Masood Tayebi is the Founder of BioDuro. He currently serves as CEO of a nationwide real estate portfolio and is a Partner and Chief Executive Officer of the Bridgewest Group. Prior to BioDuro, Dr. Tayebi was Co-Founder and Chairman of Wireless Facilities, Inc. (NASDAQ: WFI), a global leader in telecommunications outsourcing.

Achievements
  • Co-Founder of Wireless Facilities, Inc.

  • Co-Founder of BioAtla, LLC

  • Recipient of the Ernst and Young 2000 Entrepreneur of the Year award in San Diego

This will close in 0 seconds

Kewen Jin
Kewen Jin, PhD

Director, Operating Partner

This will close in 0 seconds

Amit patel
Amit Patel

Director, Operating Partner

Amit Patel has twenty years of healthcare industry experience with publicly-traded, private equity-backed, and start-up companies in the capacity of executive, board member, advisor, and investor.  He is currently Executive Chairman of Azurity Pharmaceuticals (a NovaQuest Capital Management portfolio company) and a board member at BioDuro (Advent International portfolio company), Tergus Pharma (Great Point Partners portfolio company) and Calyptus Pharma.  Recently, Amit was SVP & President of Dosage Form Solutions at Capsugel, a KKR portfolio company (purchased from Pfizer in 2011 and sold to Lonza in 2017).   

Prior to Capsugel, he worked at Dr. Reddy’s Laboratories, Inc. as EVP & Head of North America, and SVP & Head of Global Corporate Development & Strategic Planning. Earlier, Amit was VP of Corporate Development at CTIS, Inc., and Co-founder & CEO of MedOnTime, Inc. (acquired by CTIS).  He started his career as a strategy consultant with Marakon Associates. Amit holds an M.B.A. degree from Harvard Business School, a B.S. degree in Economics from the Wharton School of Business, University of Pennsylvania, and a B.A.S. degree in Systems Engineering from the Moore School of Engineering, University of Pennsylvania.

This will close in 0 seconds

Haijun Dong
Haijun Dong

Chief Executive Officer

Dr. Haijun Dong currently serves as global CEO of BioDuro-Sundia. He previously was CEO for over 5 years at PharmaBlock Sciences Inc., a public company listed in the Shenzhen Stock Exchange (300725.SZ). The positions he held prior to PharmaBlock includes, among others, Senior Scientist at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut; Senior Principal Scientist at Roche in Nutley, New Jersey; Head of DMPK and Drug Safety at Roche China R&D Company in Shanghai; Chief Operating Officer of Eli Lilly China R&D Center in Shanghai.

Dr. Dong received his PhD in organic chemistry from the University of Washington in Seattle, Washington, and MBA from China Europe International Business School in Shanghai. 

This will close in 0 seconds

Teo Nee Chuan
Teo Nee Chuan

Chief Financial Officer

Teo Nee Chuan joined us in May 2021 as chief financial officer. Prior to joining us, he was chief financial officer of Huazhu Group from November 2015 to May 2021, and was the chief financial officer for Rnomac International Limited, from November 2011 to August 2015. Mr. Teo worked in DDB Greater China Group, was appointed as the chief financial officer in September 2009, and was additionally appointed as the director of operations in January 2011. He previously served in Focus Media Group and was appointed as the financial deputy director in June 2007. Prior to that, from September 1994 to May 2007, Mr. Teo worked at Ernst & Young and Ernst & Young Business Services Ltd. in various positions in Kuala Lumpur and Toronto, including as a senior manager in the Transaction Advisory Services. Mr. Teo has been an independent director of 111, Inc. (a company listed on the NASDAQ, ticker symbol: YI) since September 2018. Mr. Teo received his Bachelor of Science in Accounting and Financial Analysis degree from The University of Warwick in the United Kingdom in July 1994. He is a Chartered Certified Accountant in the United Kingdom, who has obtained his qualification in July 1998 from The Association of Chartered Certified Accountants, and is a Certified Public Accountant in the United States and Hong Kong, who has obtained his qualification from American Institute of Certified Public Accountants in May 2002 and Hong Kong Society of Accountants in October 2003, respectively.

This will close in 0 seconds

TJ
TJ Deng, PhD

President, Discovery

Dr TJ Deng joined BioDuro in the initial stages of the company and helped BioDuro grow to an industry leading discovery services organization. He established and managed several scientific departments, including DMPK, before transitioning to a leader of the business and operations functions. Prior to joining BioDuro, Dr. Deng spent six years at PPD, in positions with increasing responsibilities from scientist to scientific manager.

Achievements

 

 

  • Developed the extractable/leachable capabilities at PPD
  • 18 years industry experience

This will close in 0 seconds

Kent Payne
Kent M. Payne, PhD

Chief Executive Officer

Kent is distinguished as a business operator and leader in areas of sales, commercial manufacturing and product development. He has extensive executive experience in M&A as well as successfully running, start up, growth and turn around businesses. This includes both Fortune 500 and Private Equity environments. He combines strong business leadership, successful P&L track record, and technical background to strategically lead and grow enterprise value across Biotechnology and Pharmaceutical market segments. He has successfully led the geographic expansion of businesses into Europe, Asia, and South America in addition to the United States.  He currently serves as CEO for BioDuro-Sundia, LLC (an Advent International company). He also currently serves as a board member for Goodwin Biotechnologies (a Signet Healthcare company). 

Prior Roles

  • President, Global CMC Solutions BioDuro-Sundia, a global
    CRDMO
  • CEO Socorro Pharmaceuticals, LLC, a generic pharmaceutical
    company
  • President Americas, Qualicaps Inc.(a Mitsubishi Chemical Holdings subsidiary)
  • Principal Consultant and Partner at CoreFactor LLC, providing executive strategic, licensing and operational advisory services to clients.
  • Vice President/General Manager Catalent Pharma Solutions, Inc. (a Blackstone Group company formed in 2007, formerly part of Cardinal Health)
  • Progressive leadership responsibility at: Novartis, Monsanto and G.D. Searle.  

Prior Brand Position

  • Board Advisor Vitruvias Therapeutics
  • Board Member Qualicaps, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board member Technophar, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board Advisor, Corporate Strategy Office, Life Science Institute
    Inc. (a wholly owned subsidiary of Mitsubishi Chemical Holdings)
  • Non-executive Chair and Board Member PDS Biotechnology·        (PDSB: NASDAQ)

This will close in 0 seconds

John Phillips
John Phillips

Vice President, Business Development (US & EU)

Coming soon…

Achievements

 

  • Coming soon…

This will close in 0 seconds

Roy Xu
Roy Xu

Chief Strategy Officer

Roy has over 25 years of healthcare industry experience.  He started his career as an orthopedic surgeon.  Roy joined Eli Lilly as a sales rep in 1997.  Since then he has had various roles in market research, business intelligence, BU head, strategy, regional general management, business development etc., both at Eli Lilly and Boehringer Ingelheim (BI).  Roy also spent more than two years in Germany where he was BI’s Director of Corporate Business and Enabling Strategy.

Roy obtained a bachelor’s degree in Clinical Medicine at Zhejiang Traditional Chinese Medicine University, and an MBA from Zhejiang University.

Achievements

 

  • 25 years of healthcare industry experience including Eli Lily and Boehringer Ingelheim. 
  • Former Director of Corporate Business & Enabling Strategy at oehringer Ingelheim in Germany.

This will close in 0 seconds

San Diego

San Diego - BioDuro-Sundia

Our San Diego site is our corporate headquarters. The facility is home to BioDuro-Sundia’s drug product development technologies and has 9 GMP clean rooms. Development and manufacturing operations are conducted for projects up to Phase III clinical trials.

Size: 44,000 sq. ft.
Featured capabilites: Tableting, Coating, Hot Melt Extrusion, Spray Dried Dispersion

11011 Torreyana Rd.
San Diego
CA 92121
United States

This will close in 0 seconds

Beijing

BioDuro Beijing

Operating since 2006, our Beijing site is home to BioDuro-Sundia’s first wet chemistry operations. With 300 regular fume hoods and 18 scale-up chemistry hoods the Beijing facility houses most of BioDuro’s chemistry operations, while also hosting labs for biology and monoclonal antibody discovery.

Size: 100,000 sq. ft. 
Featured capabilities: Radioactivity Lab, Monoclonal Antibody Discovery, Medicinal Chemistry

No. 29 Life Science Park Road
Changping District Beijing,
102206
P.R. China

This will close in 0 seconds

Shanghai-Waigaoqiao

BioDuro- Shanghai Facility

Established in 2012, BioDuro-Sundia’s Shanghai facility has been growing with its departments. The cutting edge facility contains labs for ADME, bioanalysis, in vitro assays and translational research. The site includes a 18,000 sq. ft vivarium and 20,000 sq. ft of office space.

Size: 92,000 sq. ft.
Featured capabilities: Scale-up Chemistry, Discovery Biology, DMPK, In Vivo Pharmacology

No. 233 North Fu Te Road
Waigaoqiao Free Trade Zone
Shanghai, 200131
P.R. China

This will close in 0 seconds

Cathy Yen
Cathy Yen

Director, Operating Partner

Cathy joined the Board of Directors of BioDuro-Sundia in 2020, with the Advent-led acquisition of Sundia and creation of BioDuro-Sundia. Prior to that, she was Chairman of the Board at Sundia Meditech Group, where she was the key architect of Sundia’s strategic vision and growth. Under her leadership, Sundia solidified its position as one of the leading pre-clinical CROs in China.

Prior to Sundia, Cathy had a distinguished career as a seasoned venture capitalist, having led numerous investments in high-growth companies in Asia. Cathy served as a Partner of AsiaVest Partners, TCW/YFY Ltd., a global venture capital firm, for over a decade, Vice President at Global Financial Services, Vice President at Crimson Ventures/Chinatrust Bank and Senior Manager at Fortune Capital. She brings over 20 years of experience in corporate finance, accounting, strategic planning and private equity investments. 

This will close in 0 seconds

Wuxi

Wuxi - BioDuro

Established in 2019, BioDuro-Sundia’s fully integrated discovery facility located at the heart of Jiangsu Wuxi Life Science & Technology Industrial Park with plans of growing staff to 1000+ scientists.

Size: 300,000 sq. ft.
Featured capabilities:
Discovery Chemistry & Biologics, Biology, DMPK, Pharmacology, CMC Services

no.1699,Huishan avenue
Huishan Economic 
Development Zone,Wuxi
P.R. China

This will close in 0 seconds

Hebei

Hebei - Sundia

Established in 2011, this pilot plant this handles mg to kg scale up.

Size: 45,208 sq. ft.

Featured capabilities: SFFS Chemistry: mg to kg scale up
(150 hood)

238 Changjiang Road
Shijiazhuang,
Hebei province
P.R. China

This will close in 0 seconds