What Happens in Successful Optimizations? A Survey of 2018-2024 Literature
Paul D. Leeson
https://doi.org/10.1021/acs.jmedchem.5c03171
During hit-to-lead and lead optimisation phases, physicochemical properties are optimised to produce molecules with acceptable DMPK profiles. Previous analyses of pre-2000s data showed that on average, molecules become larger and more lipophilic during these phases. In this paper, 478 drug candidates from 2018 to 2024 were compared to their “start compound”. It was found that, on average, lipophilicity did not change. While the average molecular weight, number of H-bond acceptors, and sp3 carbon atoms all increased.
Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C
Genentech, Wuxi Apptec
https://doi.org/10.1021/acs.jmedchem.5c02272
KRAS G12C inhibitors, which target the switch-II pocket, are a hot topic in drug discovery. Several companies are trying to rival the approved sotorasib and adagrasib and produce a best-in-class inhibitor. This paper details Genentech’s attempt at this, detailing the discovery and characterisation of Divarasib (GDC-6036). They describe their optimisation of binding in the “back-pocket” to drive down potency into the sub-nanomolar range.
Normalizing Covalent Potency for Electrophilicity with Ligand Reactivity Efficiency
Vividion Therapeutics
https://doi.org/10.1021/acs.jmedchem.5c01803
kinact and KI are key values used to describe the potency of irreversible covalent ligands. It was thought that increases in kinact (warhead reactivity) were undesirable, as it would lead to off-target binding and metabolic instability. However, Vividion (and others) have found this not to be the case, with several compounds displaying excellent selectivity with a large kinact and modest KI. This is rationalised by understanding that kinact depends not only on the reactivity of the warhead, but also on its position relative to the reactive amino acid. They introduce the ligand reactivity efficiency (LRE) concept, which represents the kinetic selectivity for the on-target protein compared to a generic thiol (glutathione).
Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors
PROTACs often fall outside the Rule of Five chemical space. This makes designing orally bioavailable compounds challenging. The chameleonic properties of some PROTACs are thought to be key for oral adsorption. In this article, different experimental chameleonicity parameters were evaluated for compounds with known mouse PK data from the AstraZeneca portfolio. They found that none of these parameters could be used to rationalise oral bioavailability. Instead, they found the efflux ratio in the Caco-2 assay to be more useful for filtering out compounds with poor bioavailability.
BBB-Permeable PROTACs: Where Do We Stand?
University of Torino
https://doi.org/10.1021/acsmedchemlett.5c00768
The same properties that hinder the oral bioavailability of PROTACs also hinder their ability to cross the blood-brain barrier and act on the CNS. This perspective analyses 30 publications relating to CNS-targeted degraders. They found that there is a lack of consistent design and testing strategies for these molecules.
Smallest Bicycles in Medicinal Chemistry: Where Are We Now?
Bicyclic carbon rings such as bicyclo[1.1.1]pentane (BCPs) and spiro[3.3]heptane have become increasingly common in medicinal chemistry in recent years. This is due to their ability to act as phenyl bioisosteres. These compounds often display higher solubility and metabolic stability than their phenyl counterparts. However, most small bicycles remain unexplored. This article reviews their application to bioactive molecules, as well as the commercial availability of these building blocks.
A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader
AstraZeneca, Pharmaron
https://doi.org/10.1038/s41467-026-70663-1
Thalidomide and related analogues are used in PROTACs to recruit CRBN, an E3 ligase which is commonly used for targeted protein degradation. On its own, thalidomide binds to CRBN and recruits proteins (neosubstrates), which are subsequently degraded. The degradation of several transcription factors is behind thalidomide’s teratogenic effects, as well as bone-marrow and haematological toxicities. Using these compounds in PROTACs could mean introducing the same safety liabilities of thalidomide-like compounds. This study shows that PROTACs based on these compounds can degrade proteins associated with bone-marrow and haematological toxicities. It also describes new alternative CRBN binders based on a dihydrouracil core that do not exhibit this effect.
Disulfide tethering reveals cryptic pockets in oncogenic KRAS
Frederick National Laboratory for Cancer Research
https://doi.org/10.1038/s42004-026-01992-x
Disulfide tethering is a screening approach that uses chemical libraries containing a disulfide group attached to a variety of ligands. The disulfide group can undergo disulfide exchange with either native or engineered cysteines within the protein. This approach has been used to discover ligands for targets where traditional methods have failed. It was also used to discover the first druggable pocket on KRAS, now known as the switch II pocket. In this work, disulfide tethering was used again to identify unreported cryptic pockets on KRAS that could be exploited for the development of new inhibitors.