Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human Cancers

This paper addresses one such target, where we have 2 members of the SMARCA gene family, SMARCA-2 and SMARCA-4, which encode essential catalytic proteins that regulate gene expression, deal with DNA damage repair, enable normal cell growth and suppress tumour formation. Deactivating mutations in SMARCA-2 or SMARCA-4 can lead to aggressive cancers while deactivation of both leads to cell death, this is an example of the concept of synthetic lethality where the interaction of both genes can lead to an altered phenotype (cancer) or cell death. At this point we have found a key weakness in the defences of the SMARCA-2/4-deficient cancer cell: with one of the SMARCA genes out of action, genetically, the survival of the cancer cell becomes theoretically dependent on the other SMARCA gene. If we were to take this one out with a pharmaceutical intervention, the cancer cell dies.

In the literature, there are small molecule binders and inhibitors of the SMARCA-2/4 ATPase domains. However, due to the high sequence homology between the encoded proteins, selectivity between SMARCA-2 and SMARCA-4 has not been achieved by a small molecule inhibitor, leading to both isoforms targeted, resulting in toxicity.

To address this challenge, researchers have turned to PROTAC degraders, which rely on the formation of ternary complexes between the ligand, the protein of interest (POI) and the recruited E3 ubiquitin ligase. Among the advantages in moving to a PROTAC approach is the fact that ternary complex formation relies not just on the residues in the ligand-POI binding site, but interfacial residues that might reveal important differences between proteiniso forms. Indeed, several PROTACs that display selective degradation of SMARCA-2 currently exist, but these are based on the von-Hippel–Lindau (VHL) E3 ligase and are not orally bioavailable. So, the authors of this paper took it upon themselves to find an orally bioavailable PROTAC that maintains degradation potency and selectivity for SMARCA-2 to use against SMARCA-4-deficient tumours.

Their previously-discovered wacky Spiro pentacyclic SMARCA-2 recognition element did not require much optimisation, the focus in this work was on the E3 recruiter and the linker. The choice of E3 ligase recruiter happens to be key for achieving good oral absorption, it turns out that VHL-based PROTACs rarely display high oral bioavailability (see the excellent review by Kihlberg et al here). and only Cereblon-based PROTACs generally do. For maintaining selectivity towards SMARCA-2 degradation, optimisation of the PROTAC linker played a surprisingly large role, outcomes such as this typically invokes peculation as to the distance between the POI and the E3 ligase in the ternary complex, and the overall rigidity of the system.

One key step in this story was a particularly effective CH2→O scaffold-hop in a spirocyclic cyclohexane/piperidine PROTAC linker system. This move achieved a SMARCA-2 selectivity boost and dropped the pKa of the piperidine enough to get the oral bioavailability over the line.