Macrocyclization via Ring-Closing Metathesis in Drug Discovery & Process Chemistry
Macrocyclic molecules, containing 12 or more atoms in a ring system, are increasingly prevalent in drug discovery, with over 67 macrocyclic drugs approved so far and several notable examples of clinical success highlighted on Drug Hunter recently, including MK-0616, repotrectinib, and pacritinib. By imparting conformational restraint and reducing entropy of binding, macrocyclization can enable more…
The Molecular Glue Degrader Landscape in 2022
Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs, their bulkier bivalent counterparts, to the forefront of drug hunters’ attention. Interest in molecular…
Are Drugs Becoming More Lipophilic Over Time?
Drug lipophilicity is a core property that contributes to drug solubility, permeability, metabolic disposition, and other key properties. Increasing lipophilicity can often lead to increased affinity in relevant biological assays due to the hydrophobic nature of many protein binding pockets, but this may also increase promiscuity to off-targets. High drug lipophilicity can lead to challenges…
Small Molecule PI3K Inhibition in Oncology: What’s Been Done and What’s to Come?
PI3 kinases are part of the PI3K/Akt/mTOR signaling pathway that is downstream of Receptor Tyrosine Kinases (RTKs), G-protein-coupled receptors (GPCR), and GTPases such as KRAS. Since their identification in the 1980s, and due to their central role in cancer, the therapeutic targeting of the phosphatidylinositol-3-kinase (PI3K), and more generally, the PI3K/Akt/mTOR axis has been an…
Small Molecules from AI/ML-Focused Companies Entering the Clinic (Part II)
Despite significant investment over the past decade, only a handful of companies are now bringing clinical candidates discovered with the assistance of AI/ML forward. Though there’s a looseness to what should count as an “AI-discovered drug,” here we highlight internally-generated drug programs from companies focused on leveraging AI/ML in drug discovery, who have explicitly stated…
The Molecular Landscape of AI/ML-Assisted Small Molecule Drug Discovery (Part III)
There have been numerous reviews on the impact of AI/ML in drug discovery looking at broad numbers, but with the volume of companies in the space, few have spelled out exactly what these companies are working on to paint a picture of what the landscape of AI/ML in small molecule drug discovery actually looks like…