A data science roadmap for open science organizations engaged in early-stage drug discovery.

The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe.

The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium.

A Novel NAMPT Inhibitor-Based Antibody-Drug Conjugate Payload Class for Cancer Therapy.

Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a new mode of action for cancer-targeting antibody-drug conjugates (ADCs) with activity also in slowly proliferating cells. To extend the repertoire of available effector chemistries, we have developed a novel structural class of NAMPT inhibitors as ADC payloads. A structure-activity relationship-driven approach supported by protein structural information was pursued to identify a suitable attachment point for the linker to connect the NAMPT inhibitor with the antibody. Optimization of scaffolds and linker structures led to highly potent effector chemistries which were conjugated to antibodies targeting C4.4a (LYPD3), HER2 (c-erbB2), or B7H3 (CD276) and tested on antigen-positive and -negative cancer cell lines. Pharmacokinetic studies, including metabolite profiling, were performed to optimize the stability and selectivity of the ADCs and to evaluate potential bystander effects. Optimized NAMPTi-ADCs demonstrated potent in vivo antitumor efficacy in target antigen-expressing xenograft mouse models. This led to the development of highly potent NAMPT inhibitor ADCs with a very good selectivity profile compared with the corresponding isotype control ADCs. Moreover, we demonstrate─to our knowledge for the first time─the generation of NAMPTi payload metabolites from the NAMPTi-ADCs in vitro and in vivo. In conclusion, NAMPTi-ADCs represent an attractive new payload class designed for use in ADCs for the treatment of solid and hematological cancers.

Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179.

Mitochondria are key regulators of energy supply and cell death. Generation of ATP within mitochondria occurs through oxidative phosphorylation (OXPHOS), a process which utilizes the four complexes (complex I-IV) of the electron transport chain and ATP synthase. Certain oncogenic mutations (e.g., LKB1 or mIDH) can further enhance the reliance of cancer cells on OXPHOS for their energetic requirements, rendering cells sensitive to complex I inhibition and highlighting the potential value of complex I as a therapeutic target. Herein, we describe the discovery of a potent, selective, and species cross-reactive complex I inhibitor. A high-throughput screen of the Bayer compound library followed by hit triaging and initial hit-to-lead activities led to a lead structure which was further optimized in a comprehensive lead optimization campaign. Focusing on balancing potency and metabolic stability, this program resulted in the identification of BAY-179, an excellent in vivo suitable tool with which to probe the biological relevance of complex I inhibition in cancer indications.

Discovery of a hidden transient state in all bromodomain families.

Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here, we combine extensive molecular dynamics simulations, Markov state modeling, and available structural data to reveal a transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the αA helix, opening a cryptic pocket that partially occludes the one associated to histone binding. By analyzing more than 1,900 experimental structures, we unveil just two adopting the hidden state, explaining why it has been previously unnoticed and providing direct structural evidence for its existence. Our results suggest that this state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA-binding mode.

Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo.

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.

[Assuring the quality of continuous professional development: An analysis of accreditation documents of the chambers of pharmacists in Germany]. / Qualitätssicherung in der pharmazeutischen Fortbildung: Eine Analyse der Akkreditierungsunterlagen der deutschen Apothekerkammern.

Accreditation of continuous professional training events is an important means to ensure quality. In Germany, the chambers of pharmacists accredit these events, i. e., they check the documents that the organizers of these events provide. The aim of this investigation was to compare the accreditation documents that the chambers of pharmacists publish on their websites. We developed explicit rating criteria concerning the categories quality of content, conflict of interest and sponsoring. The analysis revealed a huge discrepancy between the individual chambers of pharmacists and also in the way they addressed different items. The Federal Chamber of Pharmacists revised its accreditation requirements in early 2019, which raised the rating. However, there is still room for improvement. To ensure the quality of pharmaceutical continuous accreditation, the chambers of pharmacists should work towards establishing more stringent and uniform accreditation requirements.

Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.

Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

[Four numbers and a bit more basic knowledge of mathematics]. / Vier Zahlen und noch ein bisschen mehr Mathe. Der Unterschied zwischen Chance und Risiko.

In addition to relative risk, relative risk reduction and absolute risk reduction there circulates another effect size for binary endpoints in the scientific medical literature: the odds ratio. Relative risk and odds ratio are alternative ways of reflecting study results. Both, relative risk (RR) and odds ratio (OR), can easily be calculated from the "2 x 2-table". Advantage of OR: odds ratios can be calculated in every type of controlled study design, including retrospective studies. Furthermore, odds ratios--the biostatisticians are swarming--offer beautiful mathematical properties and therefore are often used in meta-analysis as an effect size for calculating a pooled estimate of the results of different studies with the same clinical question. Disadvantage of OR: In clinical studies the presentation of the results as "odds ratios" may result in an overestimation of the intervention effect. This article shows the difference between ""chance" and "risk" and how odds ratio and relative risk are associated.

[Four numbers and basic knowledge of mathematics]. / Vier Zahlen und ein bisschen Mathe. Das Einmaleins zum Berechnen von Effektmassen.

Results of clinical trials are presented in different expressions of risks: baseline risk, relative risk (RR), relative risk reduction (RRR), absolute risk reduction (ARR), or risk difference (RD). In this article of our series about the basics of evidence-based medicine we show how results of clinical trials are calculated based on the 2 x 2-table. The 2 x 2-table usually contains all information needed to calculate the main study results. Adequate interpretation of the results/treatment effects is the basis for evidence-based advices in pharmaceutical practice.

[Why bother with regression models?]. / Warum wir uns mit mathematischen Modellen herumplagen müssen. Hazard-Ratio, Hazard-Funktion und Cox-Regression.

In the last article, you learned about the interpretation of survival curves. This article is about the comparison of "survival" - or the time to any defined event. Two survival curves can be summarized with the hazard ratio, which is discussed in more detail in this article. In order to compare the "survival"of two treatment groups - particularly in non-randomised studies - additional variables (potential confounders) must be taken into account. This is done using a regression model, the so-called Cox-regression. After reading this article, hopefully these terms are more familiar to you.

[About the certainty of study results. What p-value and confidence intervalls tell us on it]. / Uber die Sicherheit von Studenergebnossen. Was uns p-Wert und Konfidenzintervall verraten.

In clinical trials data of individuals are collected, who are subjected to different treatments under controlled conditions. These studies investigate differences between interventions, and their results--provide the basis for clinical decision making in individuals or for policy decisions concerning entire patient populations. This requires reliable results. How confident a result of the study actually is, is illustrated by using various statistical parameters: p-value or confidence interval. What these parameters are and how to interpret them, is the objective of this article.

[The number needed to treat (NNT) and the number needed to harm (NNH)]. / Number needed to treat (NNT) und Number needed to harm (NNH). Weitere Abkömmlinge der Vier-Felder-Tafel.

In our previous articles we introduced the relative and absolute expressions of risk: baseline risk, relative risk (RR), relative risk reduction (RRR), absolute risk reduction (ARR), or risk difference (RD). The "number needed to xy" is another concept to describe the results of a clinical trial. Depending on the investigated problem the "number needed to xy" is the "number needed to treat", the "number needed to harm", the "number needed to vaccinate", or the "number needed to screen". In this article of our series we introduce the number needed to treat (NNT) and the number needed to harm (NNH) as a method to characterize the difference of two compared therapy options. As the other effect sizes the NNT and NNH can be used to inform patients about the expected benefit (or harm) of different therapy options.

[Painting by number--Survival curves and Kaplan-Meier method]. / Malen nach Zahlen. Von Uberlebenszeit-Analysen und Kaplan-Meier-Kurven.

Survival curves plot percent survival as a function of time. Results of clinical trials are often presented as survival curves. However, the purpose of survival analysis is not, as the name suggests, limited to "survival". Rather, it can concern the time to any defined event, desired or undesired. The me- thod behind these curves may be tricky; "reading" of the curves, however, is simple and intuitive. And with a few basic skills misinterpretations can usually be avoided.

[Instructions for aggregated evidence: Systematic reviews and meta-analyses (part 1)]. / Gebrauchsanweisung für konzentrierte Evidenz. Von Reviews, systematischen Übersichtsarbeiten und Metaanalysen (Teil 1).

High-quality, up-to-date, systematic reviews comprehensively summarize the evidence from clinical studies for a focused clinical question. A meta-analyses is a quantitative summary of results from individual studies and often part of a systematic review. Important features of a systematic review are a focused research question, a comprehensive, reproducible search for primary studies, selection of studies using clear and transparent eligibility criteria, and a standardized critical appraisal of the methodological quality of included studies.

[Instructions for aggregated evidence: About reviews, systematic reviews and meta-analyses (part 2)]. / Gebrauchsanweisung für konzentrierte Evidenz. Von Reviews, systematischen Übersichtsarbeiten und Metaanalysen (Teil 2).

Valid systematic reviews are essential for a safe navigation through the existing literature on a specific clinical topic. In the second part of our training to "Reviews, systematic reviews and meta-analyses", we explain how the results of systematic reviews and meta-analyses should be presented and how they should be interpreted. We describe the forest plot, with which you can get a quick overview of the results of numerous studies, the funnel plot, which can be useful for identifying a publication bias, and report on sensitivity and subgroup analyses, which are of great importance to discover the source of heterogeneity between individual studies. Finally, at the end of our article series, we hopefully convinced you of the importance to make up your own mind about the interpretation of the results of aggregated evidence.

[The information flood--a multicomponent mixture. Analytical methods for the extraction of valid information]. / Die Informationsflut--ein Vielstoffgemisch. Die analytischen Methoden zur Extraktion valider Informationen.

Over the centuries some individual scientists have challenged their knowledge, believes and behaviour. The common knowledge developed very fast, but the challenge still remains to ask the question "what do we really know"? And "what is the basis of our decisions and recommendations?" The scattered individual efforts finally advanced to a consolidated methodology--known as "evidence based medicine". This is the first article of a series to get German speaking pharmacists familiar with the basic concepts of evidence based methodology. The series gives some examples how the concept of evidence based medicine can be implemented in pharmaceutical practice.

[Navigation aid through the information overload]. / Navigationshilfe durch die Informationsfluten.

We live in the modern information society. "To be informed" has a crucial impact on the personal, professional, economic and social development. The knowledge of things and their relationships is essential for acute decisions as well as for long-term planning. And at no time it was easier to get the information required within shorter time periods--no matter to whatsoever. The offer of information of the World Wide Web is inexhaustible. This also applies to information about all possible therapeutic and pharmaceutical issues. But is the information found reliable, too? And are easily accessible sources credible? Can we deal with the information overload at these days or do we actually risk paddling only on the surface of the "information-sea", without ever perceiving the actual information depth and width, less to use it? How can we protect being taken in by marketing strategies? The present article describes a structured proceed when seeking literature to find useful medical and pharmaceutical information in a time saving manner.

[Evidence-based pharmacy - Assessement of quality and clinical relevance of study results]. / Qualitätsbewertung klinischer Studien. Ergebnisqualität: Wie man die Spreu vom Weizen trennt (Teil 2).

The critical appraisal of a study publication includes several steps: quality inspection of the study methodology, examination of the results, assessments of benefit and harm for the individual patient. If the first step of the "critical appraisal" determines, that different sources of bias were successfully eliminated or minimized in the study conduct, it is worthwhile to work through the article completely. In the second step, the size and confidence of the study results have to be examined in detail. Different outcome measures are used to describe the effect of an intervention in clinical trials. However, not all endpoints studied, or differences that are found between treatment groups, are important for the decision making of a patient. In the last step, the study results are interpreted for the individual patient in terms of the expected ben- efits and possible harms. While the control of methodical quality and the effect size of study outcomes may be based on formal criteria, professional value judgement is necessary for the transfer of study results to an individual patient, by which a recommendation can be made, adapted to the individual circumstances, needs and expectations of the patient.