Innovations Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis Christopher J. Helal,*,† Mark Bundesmann,† Susan Hammond,† Melissa Holmstrom,‡ Jacquelyn Klug-McLeod,† Bruce A. Lefker,§ Dale McLeod,† Chakrapani Subramanyam,† Oleg Zakaryants,∥ and Sylvie Sakata*,‡ †
Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States Worldwide Research and Development, Pfizer Inc., 10770 Science Center Drive, San Diego, California 92121, United States § Worldwide Research and Development, Pfizer Inc., 1 Portland Square, Cambridge, Massachusetts 02139, United States ∥ MilliporeSigma, 6000 N. Teutonia Avenue, Milwaukee, Wisconsin 53209, United States
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‡
ABSTRACT: Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates. We believe that this model can be of benefit to companies of all sizes that are engaged in drug discovery by reducing cost, increasing diversity of analog molecules in a time-conscious manner, and reducing BB inventory. More efficient use of BB by customers may allow commercial vendors to devote a greater portion of their resources to preparing novel BB that increase chemical diversity as opposed to resynthesizing out-of-stock compounds that are inaccessible within company compound collections. KEYWORDS: Building blocks, parallel synthesis, library synthesis, just-in-time
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chemistry projects to facilitate their usage.4,5 At Pfizer, internal BB access has had a tremendous impact on the speed and scope of SAR exploration. In the hit-to-lead space, especially with parallel (library) synthesis, multiple project teams have gained benefit from access to Pfizer’s extensive and readily available BB collection.6−11 More recently, in our investment in DNA-encoded library synthesis, the ability to rapidly access hundreds of desirable BB that can move directly into synthesis has also been enabling.12−14 Recently, vendors have been offering significantly more and diverse BB. For example, a search of external commercial sources such as Aldrich Market Select (AMS)15 revealed attractive mono-BOC diamines, a popular BB class at Pfizer, that were available from vendors but were not in our internal compound store (Figure 1). As we considered utilizing our extant, proactive BB acquisition model, we began to recognize significant issues that limited its continued expansion. Challenges included a complex ordering process, high costs associated with bulk BB purchase and subsequent resupply upon depletion, costly storage and handling requirements,
ynthetic chemistry’s role in the drug discovery process has recently been the topic of several reviews, emphasizing the limitations of current methodologies and the impact that new capabilities can have on expanding chemical space.1−3 In order to fully leverage the power of organic synthesis, though, there exists the operational reality that access to necessary reactants and reagents must be achieved in a timely manner in order to execute desired chemical transformations. This is especially true in medicinal chemistry where it is not uncommon for thousands of diverse analogs to be prepared in the lifetime of a project with a constant need to rapidly respond to new data with new syntheses. As a result, most large pharmaceutical companies have invested in chemical management systems to store reagents, building blocks (BB), intermediates, and final products from both internal and external sources. Benefits of these facilities to the medicinal chemist are transparent inventory, simple ordering, rapid delivery, and custom-weighed quantities in desired vial types for subsequent chemistry. Each of these attributes contributes to the efficient conversion of a proposed chemical transformation into a real experiment that can generate potential drug candidates. These inventory systems increase productivity and have led most biopharmaceutical companies to purchase and internally stock BB and chemical reagents that have broad utility across medicinal © XXXX American Chemical Society
Received: May 6, 2019 Accepted: July 5, 2019 Published: July 5, 2019 A
DOI: 10.1021/acsmedchemlett.9b00205 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Second, we wished to purchase just the BB quantities needed for the current synthetic scheme (e.g., 100−300 μmol) (Table 1, Pt. 2). This would avoid storage associated with buying excess of a BB, ensure quality control provided by the vendor, and facilitate chemistry execution by removing a BB weighing and transfer to reaction vials. This is especially important when 10s or 100s of BB are ordered at one time. Gratifyingly, multiple vendors agreed to engage with us in this endeavor. To obviate potentially lengthy quoting processes and provide cost transparency for each BB, we wanted to establish a simple set price/unit measure (e.g., 100−300 μmol) (Table 1, Pt. 3). Negotiations were successfully executed with each vendor agreeing to participate in this initiative on pricing across different quantities that are commonly used in library synthesis: 0−100 μmol, 100−200 μmol, and 200−300 μmol. It was expected that the difference in price per BB would even out over large numbers of purchases. While the cost on a per milligram basis was higher for the up to 300 μmol of BB needed for most library chemistry relative to the standard vendor quantities (e.g., 1 g), the lower ordered quantity led to significantly reduced prices for each order. This would allow us to increase diversity of BB purchased for specific syntheses while limiting the cost. The flexibility gained from this average BB pricing model for set unit amounts allowed us to move with speed and predictability for “just-in-time” orders. The advantage from our suppliers would be the larger number of BB requested and return business over time as BB end up being selected for scale-up of interesting final products. AMS would charge a fee per ordered compound to support the logistics-registration-management process from order to final delivery, which would be offset for Pfizer by the overall savings of this novel approach. We would be gaining efficiency in the process overall with a single purchase order working with AMS and a single process operationally to deliver “just-in-time” BB for synthesis. We recognized that it would be important for chemists to have a clear understanding of what BB are available within the agreed delivery time through this model (Table 1, Pt. 4). Thus, we specified that the vendors would manage the reliability of their BB inventory to support >80% on time order fulfillment. We would ideally incorporate the “just-in-time” vendor BB inventory list into our internal systems to enable a single, seamless BB searching process. When designing libraries, it is common to select one representative BB from a group of structurally related BB. The unfilled delivery of a selected BB would therefore lead to an untested hypothesis during library synthesis and would need to be minimized. AMS would provide the structural inventory data from participating BB suppliers monthly that could be incorporated into our inventory system and tagged to show these BB were from external parties. If a vendor BB was also represented in the Pfizer collection with sufficient inventory for the chemist’s request, the system would show the Pfizer batch for ordering, if this was the chemist’s preference. In cases where a vendor BB could be desirable over an internal one (e.g., unstable BB such as sulfonyl chlorides), options to search only external BB would be incorporated. The proposed logistics process (Table 1, Pt. 5) is detailed in Figure 2. The workflow includes AMS-enabled integration of vendor BB inventory into our internal searching tool, AMS consolidation of BB from multiple vendors into a single order,
Figure 1. Representative complex and high sp3 BB in AMS from vendors that were not in Pfizer internal chemical inventory.
incomplete or total lack of BB usage which provides limited return on investment, and chemical instability of certain BB types (e.g., sulfonyl chlorides, heteroaryl halides, aldehydes, and heteroaryl boronates). To significantly increase BB access for Pfizer medicinal chemists, we sought to leverage the everincreasing availability and quality of BB from top tier BB suppliers, while working with compound aggregating partners such as the AMS program for efficiency in process and delivery. As we considered the viability of an externally focused BB purchasing model, however, the challenges of opaque vendor inventories, unpredictable delivery times, lengthy quoting processes for each compound, predefined orderable quantities (e.g., 500 mg or 1 g) that lead to overspending and underutilization, and the need to register and weigh desired amounts of materials dictated the necessity for a novel business model that could meet our needs. We recognized that a “just-in-time”16 purchasing model for BB that could recapitulate key aspects of our internal inventory system would be required to have optimal uptake by medicinal chemistry customers and identified five key criteria (Table 1). Table 1. Vendor Criteria for External Just-in-Time BB Inventory Model Pt. 1 2 3 4 5
reliable w/large numbers of desirable BB weigh custom BB quantities negotiate set price/unit BB transparent inventory, >80% order fulfillment, 1-week delivery compound aggregators support logistics
Our first step was to identify vendors that had large numbers of desired BB in stock, with inventory in locations that could enable fast delivery to our synthesis sites. Rapid and consistent delivery of the ordered BB would be essential in facilitating chemistry execution (Table 1, Pt. 1). These criteria were critical to ensure that chemists would want to utilize BB accessible via this process to prepare high-value analogs for their projects. The BB collections of vendors offering attractive BB with key functional groups (e.g., acids, amines, boronic acids, aldehydes, etc.) were assessed for potential uptake using computed physicochemical properties. Vendors having large numbers of in-stock BB were engaged to assess their willingness to participate in this venture. B
DOI: 10.1021/acsmedchemlett.9b00205 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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highlights an effective utilization of QBB beyond medicinal chemistry analog synthesis. We next analyzed QBB order totals and order frequency (Figure 3). Overall, of >14,000 QBB delivered, 10,659 were
Figure 2. Proposed external BB ordering and logistics workflow.
registration of BB for internal tracking, and delivery to our synthesis locations. With a plan in hand, we were able to identify >20 vendors with significant supplies of BB who agreed to our criteria (Table 1, Points 1−4), with AMS agreeing to play the key role of BB aggregator (Table 1, Pt. 5). We call this process Quick Building Blocks (QBB). We share herein an assessment of QBB over a 2+ year period regarding its ability to meet our desired objectives outlined in Table 1 and additional measures of utility. Critical to QBB is delivering a high percentage of ordered BB (Table 1, Point 4). In this process the chemist selects BB via our internal database, then submits orders directly to AMS to assess actual vendor availability (Figure 2). Over the past 3 years, > 89% of requested BB have been available from vendors, demonstrating the value of monthly vendor inventory being merged to our internal database (Table 2). Of those available BB, essentially 100% have been shipped, significantly exceeding our goal of >80% order fulfillment and building confidence in this process.
Figure 3. Comparison of total QBB orders to unique QBB orders and the frequency of QBB orders.
unique. Looking further at how many times each BB was ordered, 8345 BB were ordered just one time (1×), 1553 BB were ordered twice (2×), and 761 BB were ordered three or more times (>3×), which is ca. 78%, 15%, and 7% of unique BB orders, respectively. This data shows that low numbers of orders/BB are common, and in line with experiences of our pro-active BB acquisition model, purchases of BB quantities specifically for planned chemistry results in a better allocation of resource. Next, we evaluated the novelty of the QBB relative to previously registered compounds in the Pfizer compound store (Figure 4). The majority of QBB (63%) were registered for the
Table 2. QBB Ordering and Shipping Metrics for 2016− 2108 QBB requested vs available QBB shipped vs available average days shipment •US to US •US to Asia •Asia to Asia QBB orders placed
2016
2017
2018
93% 100%
93% 100%
89% 98%
1352
4 6 3949
4 6.5 3 8941
We next addressed the time from placing an order to vendor delivery of BB to the site of synthesis. With optimization, we have achieved a cycle time from order to delivery in about 6 business days (US to Asia), ∼4 days (within US), and 3 days within Asia (Table 2). This new capability has allowed QBB to be integrated with internally available BB for library synthesis with no impact on the cycle time for library synthesis vs those produced solely with internally ordered BB. We then assessed the number of total QBB orders placed on a yearly basis since we started this program (Table 2). As is apparent, we saw rapid uptake among medicinal chemists, with consistently increasing orders per year since the operation was established (mid-2016). The majority of orders supported library synthesis (data not shown). In 2018, QBB were first used to access diverse BB for DNA-encoded library synthesis. This contributed a significant increase in total orders and
Figure 4. BB batch availability in Pfizer compound store.
first time, showing that chemists were accessing novel chemical space relative to our inventory in a time and resource-sparing manner, a key goal of the process. A significant portion (32%) had been registered within Pfizer previously, but insufficient quantities were available, demonstrating the benefit of QBB to address the “just-in-time” resupply of consumed BB. Only a small portion (99% had HBA ≤ 4 and 93% had HBD ≤ 2 (Figure 5). The number of QBB that simultaneously met all four criteria was 71%. Overall, this analysis demonstrates that the QBB process is facilitating access to favored BB chemical space, making it an important addition to inventory available within our compound store. A number of multiorder BB were identified that were used across several projects (Figure 6). Assuming high usage would continue, gram quantities were purchased for our internal compound store to save cost. A rule of 2 analysis showed that all compounds met all four criteria, most being well below the targeted limit. From a general structural standpoint, these QBB contain a single ring with polar substitution and are of low MW. These features lead to minimal increase or even a
Figure 6. High-use QBB that was purchased for Pfizer internal compound store.
decrease in lipophilicity when incorporated into a template concurrent with limited MW increase, both of which are important in the medicinal chemist’s desire to identify polar and efficient-binding molecules.18,19 Many of these would be considered as standard BB to include in libraries, but their absence from our internal compound store had led them to not being used in library synthesis until QBB facilitated their inclusion.
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LEARNINGS FROM QBB MODEL IMPLEMENTATION Key lessons were learned regarding vendors and process. First, not all suppliers were able to participate in this model as they did not meet the criteria we were seeking for readily available inventory, being willing and/or able to sell smaller, custom quantities at an average price/BB or to ensure quality of monomer purity (>90%) and >80% order fulfilment. Regarding the latter point, once a vendor agreed to participate, it was essential that we partner to develop the operations with the mind-set of continuous improvement to achieve targeted efficiencies. In addition, they had to ensure specific delivery in the vial type that could accommodate both BB transfer and subsequent chemistry, which was important for facilitating synthesis. Finally, we had to align with compound aggregator AMS to ensure that the business model they offer for ordering BB was also aligned with specific suppliers who were participating in the program, as well as integration of the D
DOI: 10.1021/acsmedchemlett.9b00205 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Author Contributions
communication and logistics (order processing and receiving, BB registration in our inventory database, rapid shipping, delivery directions, and import/export standard operating procedure).
All authors have given approval to the final version of the manuscript. Notes
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The authors declare no competing financial interest.
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CONCLUSION We have observed multiple advantages from the utilization of the QBB process at Pfizer. First, we have been able to access large and diverse sets of BB in custom quantities (100−300 μmol) in a cost-effective manner relative to our previous BB purchasing model. The benefit of externalizing a portion of our BB collection has meant that we do not have to finance costly bulk prepurchasing and potential lack of usage, resupply, and storage. The high rate of order fulfillment and timeliness of delivery to synthesis sites has been critical in the uptake of this process. Furthermore, preweighed quantities of BB into desired vial types has facilitated synthesis of final analogs via library synthesis, which is significantly more efficient than if the compounds were made by traditional bench synthesis. Most final compounds that were made in a library format because of QBB would not have been possible to access working with multiple vendors, ordering bulk quantities, with unpredictable delivery schedules. While we cannot discuss in detail, the increased throughput of desired medicinal chemistry analogs has resulted in multiple examples of project impact that would not have happened in the same time frame or cost without access to QBB. We also observed that suppliers were willing to be flexible in adding more diverse BB and allowing for larger amount of BB than previously negotiated as some chemistry has necessitated this. The analysis of QBB physical properties clearly shows that chemists are accessing desired chemical space even though there is no limitation on what can be ordered from vendors. Importantly, both our compound aggregator partner AMS and vendors have worked collaboratively with us on continuous improvements to further streamline the process. We have now expanded this workflow by identifying a supplier in Asia who can quickly deliver QBB to our Asia CROs to further reduce CT. Beyond the many benefits outlined, QBB may have two additional less obvious impacts. The first is keeping inventory with vendors that can be distributed readily for chemical synthesis versus being in company compound stores where it is available only to those inside the organization. As such, this may allow vendors to spend more time preparing new BB to enable chemical space exploration as opposed to resynthesizing existing but inaccessible BB for customer orders. Second, QBB could enable academic groups to cost-effectively access pharmaceutically relevant substrates on which to explore and optimize new chemistry for greater impact of their work.20 We believe there is clear value of the QBB “just-in-time” process and that its expansion will support the ever-increasing high-throughput synthesis capabilities21−23 that are critical in pushing the boundaries of medicinal chemistry in identifying new medicines for patients more quickly and cheaply.
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ACKNOWLEDGMENTS We would like to thank the following Pfizer colleagues: Richard Connell for his support and input on the initiative, James Tornos and Lisa Thomasco for their support in negotiation and contract support with our suppliers; Steve Trudel, Steve Reith, and Jeremy Rathbun for informatics support; and Joy Yang for graphics support. The AMS team at Millipore Sigma is also gratefully acknowledged, as are our QBB partners who worked with us to create this model.
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ABBREVIATIONS AMS, Aldrich Market Select; BB, building blocks; QBB, Quick Building Blocks REFERENCES
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: chris.j.helal@pfizer.com. *E-mail: sylvie.sakata@pfizer.com. ORCID
Christopher J. Helal: 0000-0002-9091-2091 E
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