and economic challenges in order to foster continued robust biopharma research and development worldwide. Any solution that aspires to lower drug prices should also expand access to affordable insurance, streamline regulation, and spread cost and risks across all of the players in the biopharma ecosystem. While the reactive ramp up of world‐wide efforts in reaction to the SARS‐CoV‐2 pandemic was not ideal, it may contain elements (e.g. aggressive repurposing of existing therapeutics; parallel, collaborative efforts interrogating new potential therapeutics and preventatives; rapid publishing of preclinical and clinical data on open‐source platforms) that could inform on reforming drug discovery and development models [19].
Despite the somewhat dire picture painted by the challenges above, drug discoverers and developers worldwide have made some remarkable contributions to the pharmacopeia over the last decade. Advances in immuno‐oncology that unleash a patient's own anti‐tumor immunity to treat certain cancers have been revolutionary [20, 21]. The potential to couple new drugs with programmed cell death protein‐1 (PD‐1) inhibitors like Opdivo® (nivolumab) and Keytruda® (pembrolizumab) has led a veritable renaissance of research into novel immunomodulators and cellular metabolism regulators, all with the hope that they could be exploited as combination agents in cancer therapy, as well as provide insights into or be exploited for the treatment of cardiovascular and neurologic disorders. Dysfunctions in the humoral immune system that manifest as aggressive B‐cell non‐Hodgkin lymphomas are now treatable with inhibitors of Bruton's tyrosine kinase (Btk) inhibitors such as Imbruvica® (ibrutinib); Btk inhibitors with enhanced tolerability and resistance profiles are under active clinical investigation [22]. New anti‐diabetic drugs like Jardiance® (empagliflozin), a selective inhibitor of sodium glucose co‐transporter‐2 (SGLT2), have been clinically demonstrated to provide significant cardiovascular benefit [23]. The discovery and development of the hepatitis C (HCV) NS5B protein RNA polymerase inhibitor Sovaldi® (sofosbuvir) and HCV NS5A inhibitor Harvoni® (ledipasvir) led the charge to identify cross‐genotype HCV drugs that can cure infected patients in three months or less. Recent breakthroughs that have produced drugs effective against multi‐drug resistant tuberculosis demonstrate that progress can be made against decades old problems [24]. These and other groundbreaking therapies have benefited from the innovations and insights of drug discovery and development chemists. I am confident that medical researchers and drug hunters have the potential to maintain this trajectory as we move into the 2020s.
While AstraZeneca's widely cited five‐dimensional framework on research and development productivity [25] does not explicitly call out “the right chemistry” among its factors for long‐term research success, many recent advances in chemical biology and medicinal chemistry have the potential to impact those factors as we move forward. Barriers to drugging “the right target” and establishing “the right safety” are on their way to being toppled by advanced tools and technologies that allow for deliberate exploitation of allostery, the modulation of RNA biology with small molecules [26], the therapeutically beneficial manipulation of transcription factors [27], the resetting of the autophagy “rheostat” [28] and the targeted degradation of disease‐relevant proteins [29]. The last – which can be thought of conceptually as the post‐translational knockdown of proteins – is particularly intriguing today, as the first “molecular glues” and proteolysis targeting chimeras (PROTACs) have reached the clinic [30] and the field of targeted degraders promises to produce more molecules that can be put in the context of “rule‐of‐five” chemical space [31]. Our rapidly developing understanding of the complexities of human microbiome and its connection to cardiovascular, immunologic, and neurologic “health” will likely expand target space and point to new approaches for therapeutic intervention. This is tied to the re‐emergence of phenotypic drug discovery in general and all of this could be accelerated via the application of present‐day genomics tools coupled with the state‐of‐the‐art informatics capabilities.
A group of my MSD Chemistry colleagues recently rejected the position that the act of designing and synthesizing molecules is a commoditized aspect of pharmaceutical research, but rather “that excellence and innovation in synthetic chemistry continues to be critical to success in all phases of drug discovery and development [32].” This sentiment echoes the recent views of other chemists from both academic and industrial circles [33–36] and I can point to multiple times over my 35 year career where organic synthesis has indeed been a significant inspiration of my ideas (both good ones and bad ones). Looking forward, the capability exists for most industrial medicinal chemists to rapidly work through the more empirical aspects of their drug discovery projects using powerful automation tools [37] enabled by machine learning and artificial intelligence and this will likely become part of the standard academic training regimen for the next generation of drug discovery and development chemists [38]. The horizons of organic synthesis continue to expand via the continued innovation in areas of chemo‐ and biocatalysis [39], electrochemistry [40], flow chemistry [41], methods to productively disconnect carbon–carbon bonds [42], and photochemically induced oxidation/reduction chemistry [43]. These will not only afford access to new biologically interesting chemical space for medicinal chemists, but also pave future paths to design concepts. Synthesis is not (nor should it be) the only driver of molecular design and it is presently complemented by current capabilities of machine learning to understand and optimize molecular interactions as well as finely balance the molecular properties critical to bioperformance (absorption, distribution, metabolism, excretion, and toxicity) [44]. While there are currently growing pains with machine learning in drug research [45], it has the potential to positively impact future drug research efforts.
In the era when we see public figures staking claim to “alternative facts” and regularly hear claims that inconvenient or uncomfortable (but objectively verifiable) information is “fake news”, broad societal pressures and the “human element” may pose the biggest threat to continued new discoveries in drug research. In his ground‐breaking 2005 book The World Is Flat: A Brief History of the Twenty‐first Century, Thomas Friedman lays out how the digitization of information and the broad reach of the internet has led to the rapid democratization of capabilities and knowledge [46]. Anyone connected to or embedded in drug research now regularly grapples with the resulting positive and negative impacts of Friedman's flat world. While we can marvel at the power and convenience of conducting broad literature searches in seconds by simply clicking a mouse, this comes at a cost to researchers of having to discern increasingly faint signals in an exponentially expanding sea of noise. As we enhance our ability to leverage artificial intelligence [47] and exploit big data we may be able to eventually corral large quantities of disparate sets of information that is relevant to drug discovery and development, but pitfalls that can be traced to the humans behind the computers have already come to the fore [48].
I also believe that there are significant risks to future innovations posed by the fracturing of the complex research environments into discrete units and continued efforts to optimize their individual parts. This has manifested itself in a pharmaceutical “gig economy” that can reinforce a short‐term, transactional mindset and poses significant challenges to individuals who may be more accustomed to or who would thrive in more traditional research environments [49]. In order to ensure we are on the path to discovering future medicines, we must realize that the rigorous application of the scientific method coupled with savvy decision‐making is critical. The disciplined fostering of individual and group behaviors that promote innovation should be a priority. Making sure that we tolerate failure, allow for experimentation, ensure psychological safety, promote collaboration and demand that we have leaders who support all of this is crucial to have if we seek to avoid having promising research undercut by non‐productive human intervention [50].
While we in the field of medicinal chemistry and drug research and development find ourselves in an era of great challenges, I am optimistic about the future of the discipline. The chapters in this volume that detail efforts that resulted in new drugs to treat bacterial and viral infections, numerous metabolic disorders and various cancers serves as a testament to the creativity, persistence, technical skill and innovative insights of the many individuals and large teams required to make these therapeutics a reality. Beyond that, none of this would have been
