Current advances and development strategies of orally bioavailable PROTACs

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs

“…This molecule was crafted using AR ligands from the same category as those in ARD-2051 and incorporates a novel cereblon-binding molecule, TX-16. Regarding its degrading capability, ARD-1676 displays DC50 values of 0.1 nM In summary, this medicinal chemistry effort demonstrated that substantial discrepancies in PK profiles among different species could be mitigated through systematic structural optimization, which included strategies such as reducing the polar surface area and making targeted adjustments to the protein ligand, linker, and E3 ligase components [65]. ues of 11.5 nM in VCaP cells and 2.8 nM in LNCaP cells.…”

“…Given these properties, ARD-1676 is viewed as an exceptionally promising candidate for the development of treatments for AR-positive human prostate cancer [61]. In summary, this medicinal chemistry effort demonstrated that substantial discrepancies in PK profiles among different species could be mitigated through systematic structural optimization, which included strategies such as reducing the polar surface area and making targeted adjustments to the protein ligand, linker, and E3 ligase components [65]. Qin and colleagues recently reported on a promising orally available PROTAC, BWA-522 (7), which has shown efficacy in promoting the degradation of both the full-length androgen receptor (AR-FL) and the AR-V7 variant (Figure 11) [66].…”

“…These innovative structural elements combine to endow CFT1946 with exceptional oral bioavailability, demonstrated by an oral bioavailability (F%) of 89% in rats, while maintaining precise selectivity for degrading BRAF V600E. This showcases a stellar instance of how high oral bioavailability for heterobifunctional PROTACs that exceed the conventional ‘Rule of Five’ can be achieved through a strategic medicinal chemistry initiative, which includes a thoughtful design of the linker component [ 65 ].…”

Radiation responsive PROTAC nanoparticles for tumor-specific proteolysis enhanced radiotherapy

“…3 Although some PROTACs have already entered clinical trials, their relatively high molecular weight (in the range of 800–1000 Da) and undesired solubility may reduce their cell permeability and tumor accumulation. 1,4,5 The degradation of off-target proteins in normal tissues may cause systemic toxicity. Recently, PROTAC based prodrugs or smart nanoplatforms triggered by either the internal microenvironment conditions such as pH 6 and enzymes 7,8 or external stimuli such as light 9,10 and X-ray 11 have been developed to control the activation of PROTACs.…”

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

“…However, translating PROTACs into clinical settings faces challenges. The design of potent, cell-specific PROTAC molecules with favorable pharmacokinetic and safety profiles remains a critical area of research (Kargbo, 2023;Kou et al, 2023;Mukerjee et al, 2023;Zeng et al, 2023). The quest for optimal PROTACs involves balancing properties like molecular size, solubility, and bioavailability, which are pivotal for their in vivo efficacy and tolerability (Cheng et al, 2023;Liu et al, 2023;Si et al, 2023;Silva et al, 2022;Zeng et al, 2023).…”