Orally bioavailable and active degraders in the clinic
Chris De Savi ：Vice President, Head of Drug Discovery at Kymera Therapeutics
Targeted protein degradation (TPD) is a new modality which harnesses the body's natural cellular recycling machinery, the ubiquitin proteasome system to degrade unwanted proteins. The UPS comprises a series of finely orchestrated sequences involving critical enzymes called E3 ubiquitin ligases which direct the “tagging” of unwanted proteins with a molecule called ubiquitin.
Heterobifunctional degraders also referred to as PROTACs consists of a ligand for the target protein tethered through a linker to a second ligand, which binds to and recruits an E3 ligase. These molecules tend to have higher molecular weights vs typical oral drugs. The design of PROTAC degraders to achieve good oral pharmacokinetics has been a challenge for the field.
Despite these challenges, significant advances have been made recently to design both active and orally bioavailable heterobifunctional degraders. Some recent clinical examples are noted here -
- ARV-110, an androgen receptor (AR) degrader for the treatment of metastatic prostate cancer (PC). It degrades AR in various PC cell lines. It is orally bioavailable across multiple doses in the clinic.
- ARV-471, an estrogen receptor (ER) degrader for the treatment of ER+ breast cancer. It degrades ER in ER +ve BC cell lines. It is orally bioavailable across multiple doses in the clinic.
- KT-474, an IRAK4 degrader for the treatment of various indications including Hidradenitis suppurtiva (HS) and AD. KT-474, to date, has demonstrated oral bioavailability, predictable and dose-dependent plasma exposures, and a half-life supportive of oral daily dosing. Following a single oral dose, IRAK4 reduction was observed as early as 8 hrs post dose, reaching maximal reduction at 48-72 hrs, and was sustained for at least 6 days with subsequent recovery towards pre-treatment baseline across all dose groups.
- NX-2127, a BTK and IMiD substrate degrader for the treatment of various B-cell malignancies. Oral dosing of NX-2127 degrades BTK in cynomolgus monkeys. It induces significant degradation of BTK in 4 hrs and >90% degradation through 24 hrs post dose. Once daily, oral dosing of NX-2127 maintains suppression of BTK protein levels throughout the duration of the study.
- AR-LDD, an orally bioavailable AR degrader for the treatment of prostate cancer. It causes degradation of AR, prevents AR-mediated signaling and inhibits the proliferation of AR-overexpressing tumor cells.
The field of TPD is making amazing progress and these molecules demonstrate that oral bioavailability can be designed into this modality directly leading to pre-clinical and clinical activity.