David E. Heppner

A Structural Perspective on Non-covalent Targeting of Conserved Polar Residues in Protein Kinases

Nader N. Nasief, Kishan B. Patel, Blessing C. Ogboo, David E. Heppner

Abstract All protein kinases contain conserved amino acid residues that bind the ATP substrate molecule and promote catalysis. As an intensely pursued drug target class, kinase inhibitor development is often streamlined by the utilization of three-dimensional structural data and binding modes to …

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Über die Bindungsstelle hinausgedacht: Ein sich selbsteinkapselnder Kinase‐Inhibitor modelliert seine Bindetasche und erzielt so Selektivität

Nico J. Seidler, Monica R. MacDonald, Athina A. Moschopoulou, Sahba Cunningham et autres

ZUSAMMENFASSUNG Selektivität ist eine wichtige Anforderung in der Entwicklung von Kinase‐Inhibitoren und das Erreichen dieser stellt nach wie vor eine große Herausforderung dar. Um neue Wege zur Erzielung von Selektivität zu ebnen, haben wir den ersten p38δ‐Isoform‐selektiven Inhibitor entwickelt, welcher im Vergleich …

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Thinking Outside the Binding Site: A Self‐Encapsulating Kinase Inhibitor Remodels Its Pocket to Achieve Selectivity

Nico J. Seidler, Monica R. MacDonald, Athina A. Moschopoulou, Sahba Cunningham et autres

Rendering kinase inhibitors selective is a strict requirement in drug development and remains a persistent challenge. To identify new routes to engineer selectivity, we have discovered a first-in-class p38δ-isoform selective inhibitor reflecting 12 000-fold selectivity improvement over currently available compounds and superior …

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Correction to “Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting”

Tahereh Damghani, Shenghan Song, Kaly S. Lin, Jianing Li et autres

Consistent Quantitative Reporting in Medicinal Chemistry

David E. Heppner, Lori Ferrins, Nouri Neamati, Angela J. Russell et autres

RecommendationsM edicinal chemistry is a discipline grounded in quantitative data.Decision-making relies on the correct use and presentation of values derived from experimental and theoretical methods.Biological assays dominate early drug discovery and frequently provide critical guidance for the optimization of a drug candidate.Structure-activity …

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Undergraduate Student Perspectives on Medicinal Chemistry and Drug Discovery Research

David E. Heppner, Ignat S. Fomin, Uriy V. Grabovyy, Tyler Hartman et autres

RecommendationsT he education of future scientists and healthcare professionals is shaped through many avenues, but immersive research experiences offer unique opportunities that expose trainees to the realities of the scientific process.Within medicinal chemistry and drug discovery laboratories, students encounter a uniquely interdisciplinary …

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Epidermal Growth Factor Receptor as a Model Drug Target for Scrutinizing the Status Quo in Drug Discovery and Chemical Biology

David E. Heppner, Monica R. MacDonald, Nader N. Nasief, Shilpa E. Naik et autres

Drug discovery scientists and chemical biologists continually seek to improve strategies for compound development. Here, we present insights derived from multiple studies of the epidermal growth factor receptor (EGFR), illustrating how this well-established target can inform practical aspects of drug discovery. Case …

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From Serendipity to Rationality: Expanding Druggability by Molecular Glue Discovery

David E. Heppner, CongBao Kang, Weijun Xu

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Abstract 4520: Development of terfenadine-derived small-molecule inhibitors of TFE3-O dimerization for translocation renal cell carcinoma.

Christian Migliarese, Mohd Abdullaha, Ilaria Delle Fontane, David E. Heppner et autres

Abstract Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer subtype with poor clinical outcome and no effective standard therapies. It is characterized by gene fusions involving members of the MiT transcription factor family, most commonly TFE3 fused to various partner …

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Small-Molecule Drug Discovery Targeting RNAs: Hope or Hype?

CongBao Kang, Hung T. Nguyen, David E. Heppner, Bin Yu et autres

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Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting

Tahereh Damghani, Shenghan Song, Kaly S. Lin, Jianing Li et autres

Inhibitors targeting mutant EGFR remain a persistent need in combating drug resistance in non-small cell lung cancer. To better understand the molecular factors involved in targeting T790M and C797S mutations, we determined X-ray cocrystal structures of fourth-generation inhibitors BI-8128 and BI-4732. Analysis …

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Structural Insights into the Potency of Brain-Penetrant EGFR Inhibitors

Abigail M. Lantry, Tahereh Damghani, Omobolanle A. Abidakun, Monica R. MacDonald et autres

An increasing focus on kinase targeting in neurological diseases has led to improvements in drug exposure within the central nervous system (CNS). Tyrosine kinase inhibitors (TKIs) targeting EGFR have gradually evolved to exhibit enhanced CNS exposure through rational design relevant to several …

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