Central Nervous System Targeted Protein Degraders

Abstract

Diseases of the central nervous system, which once occupied a large component of the pharmaceutical industry research and development portfolio, have for many years played a smaller part in major pharma pipelines-primarily due to the well cited challenges in target validation, valid translational models, and clinical trial design. Unfortunately, this decline in research and development interest has occurred in tandem with an increase in the medical need-in part driven by the success in treating other chronic diseases, which then results in a greater overall longevity along with a higher prevalence of diseases associated with ageing. The lead modality for drug agents targeting the brain remains the traditionally small molecule, despite potential in gene-based therapies and antibodies, particularly in the hugely anticipated anti-amyloid field, clearly driven by the additional challenge of effective distribution to the relevant brain compartments. However, in recognition of the growing disease burden, advanced therapies are being developed in tandem with improved delivery options. Hence, methodologies which were initially restricted to systemic indications are now being actively explored for a range of CNS diseases-an important class of which include the protein degradation technologies.

Keywords: CNS; PROTACs; targeted protein degraders.

Figure 1

The constituent parts of a PROTAC.

Figure 2

Schematic of a PROTAC bringing the POI into proximity with the UPS.

Figure 3

(A) Hook effect depicting the proportion of degraded POI when the systemic concentration of PROTAC is both too high and too low. (B) PPIs between the POI and E3 ligase. Importantly, even when PROTAC–POI affinity is weak, favourable PPIs can stabilise the ternary complex, leading to effective ubiquitination and consequent degradation.

Figure 4

Representation of the peptide PROTAC TH006.

Figure 5

Representation of a Keap1 peptide PROTAC.

Figure 6

Tau PET tracer and PROTAC analogue.

Figure 7

Second-generation Tau PROTAC degraders.

Figure 8

Effective in vitro and in vivo Tau-degrading PROTAC.

Figure 9

Two generations of mHTT-degrading PROTACs by Tomoshige et al., which showed an initial promise.

Figure 10

PROTAC targeting LRRK2 for degradation.

Figure 11

α-synuclein-degrading PROTACs.

Figure 12

C-TDP-43-degrading PROTAC, JMF4560.

Figure 13

The degradation of a substrate via the endosome–lysosomal pathway.

Figure 14

The non-specific bulk and specific degradation of cargo via the autophagy pathway.

Figure 15

The degradation of substrates using LYTACs.

Figure 16

AUTACs targeting mutant Tau for degradation.

Figure 17

Effective ATTECs targeting mHTT shown to cross the BBB.