Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities

Abstract

Small molecules designed to modulate protein function have been remarkably successful in advancing human health. As the frontiers of medicine and understanding of disease pathogenesis continue to expand, small molecule scientists must also pursue the development of novel therapeutic modalities beyond functional protein modulation to address diseases of unmet medical need. In this vein, this Perspective will highlight two emerging modalities, selective mRNA splice modulation and targeted protein degradation, as mechanisms that affect protein abundance, rather than protein function, to broaden the scope of low-molecular-weight treatable diseases. Key to the elucidation and development of these mechanisms was the interplay and contemporaneous efforts in medicinal chemistry and chemical biology. Continued research at the intersection of these two fields will be critical for the identification of novel targets and mechanisms toward the development of the next generation of small molecule therapeutics.

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

“…In diffuse large B-cell lymphoma (DLBCL), targeting BCL6, a transcriptional repressor involved in the formation of germinal centers might be a powerful tool to treat these patients [ 6 ]. In addition, small molecules were designed to target protein abundance using small mRNA splice modulation and protein degradation rather than using the inhibitory mechanism against a specific protein [ 7 ]. Other small molecules interacting with the mTOR pathway, such as icaritine analogues, bypassed the low activity and off-target limits, providing a new tool in anti-multiple myeloma (MM) therapy [ 8 ].…”

EFMC: Trends in Medicinal Chemistry and Chemical Biology

“…The last few years have seen a rapidly expanding range of chemical modalities being explored for their potential to modulate cellular pathways in novel ways, among others including the concept of modulating target expression, rather than target function. [59] Medicinal chemists and chemical biologists have frequently joined efforts to broaden the range of therapeutic principles they optimised, aiming to exploit increasingly diverse drug targets. [60] They have explored previously intractable therapeutic concepts by adding polyfunctional modalities, peptides, proteins, macrocycles, and nucleotide-based therapeutics to their low-molecular weight (LMW) armamentarium.…”

“…The last few years have seen a rapidly expanding range of chemical modalities being explored for their potential to modulate cellular pathways in novel ways, among others including the concept of modulating target expression, rather than target function [59] . Medicinal chemists and chemical biologists have frequently joined efforts to broaden the range of therapeutic principles they optimised, aiming to exploit increasingly diverse drug targets [60] .…”

Synthetic Biology and Its Potential in U.S. Medical Therapeutics: A Comprehensive Review: Exploring the Cutting-Edge Intersections of Biology and Engineering in Drug Development and Treatments

“…Furthermore, the intersection of medicinal chemistry and chemical biology, as discussed by Palacios (2022), is crucial in the discovery of novel therapeutic modalities. This includes the development of small molecules designed to modulate protein function and affect protein abundance, broadening the scope of treatable diseases.…”

“…This includes the development of small molecules designed to modulate protein function and affect protein abundance, broadening the scope of treatable diseases. The interplay of these disciplines is essential for identifying new targets and mechanisms, thereby facilitating the development of next-generation small molecule therapeutics (Palacios, 2022). In summary, the emergence of synthetic biology in modern medicine represents a paradigm shift, merging the principles of biology, chemistry, and engineering to address complex medical challenges.…”