Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders

Abstract

AB-MPS, simple multiparametric scoring function predicting oral absorption, ADME, absorption, distribution, metabolism, and excretion; BCS, biopharmaceutical classification system; BLQ, below the limit of quantification; bRo5, beyond the Lipinski's rule of 5; CNS, central nervous system; CRBN, cereblon E3 ligase; DC 50 , concentration with 50% target degradation; DDI, drug-drug interaction; D max , maximal degradation; DMPK, drug metabolism and pharmacokinetics; EPSA, experimentally determined exposed polar surface area; FaSSIF, fasted simulated intestinal fluid; FeSSIF, fed simulated intestinal fluid; GLP, good laboratory practice; IND, investigational new drug; IV, intravenous administration; HBA, number of hydrogen bond acceptors; HBD, number of hydrogen bond donors; MW, molecular weight; NRB, number of rotatable bonds; PBPK, physiological based pharmacokinetic modeling; PK, pharmacokinetics; PD, pharmacodynamics; PO, oral administration; POI, protein of interest; PPB, plasma protein binding; tPSA, topological polar surface area; RED, rapid equilibrium dialysis; SC, subcutaneous administration; SGF, simulated gastric fluid; TPD, targeted protein degraders specifically PROTACs; VHL, von Hippel-Lindau E3 ligase

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders

“…Second, there is an ongoing need for more predictive in vitro ADME assays for PROTACs. It has been noted as a general trend across multiple companies, , as well as at Arvinas, that such assays as configured for more traditional small molecules are often poorly predictive of in vivo PROTAC behavior. Third, greater attention to the potential of parenterally administered PROTACs is warranted.…”

Innovative, combinatorial and high-throughput approaches to degrader synthesis

“…It should be stated that others have found insolubility or non-specific binding to occasionally give confounding results for such high molecular weight compounds in similar assays, 7 echoing experience within GSK laboratories, and so this should be considered as a possibility when unexpected in vitro biological data is obtained. 55…”

Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?

“…PROTACs are also large molecules which extend into challenging non-traditional, “beyond rule of 5” (bRo5) property space ( Matsson et al, 2016 ; Volak et al, 2023 ). There are additional resulting challenges: (i) larger molecules can behave differently especially regarding permeability and transport ( Guimaraes et al, 2012 ; Doak et al, 2014 ; Matsson et al, 2016 ; Matsson and Kihlberg, 2017 ; Pye et al, 2017 ; Linker et al, 2023 ); (ii) available chemical space is larger; (iii) large molecules are often more conformationally complex ( Rossi Sebastiano et al, 2018 ; Mobitz, 2023 ); (iv) fewer molecules from bRo5 space have been studied; (v) those studied molecules cluster in niches (e.g., macrocycles) and represent a less even distribution ( Doak et al, 2014 ).…”

“…While the extent to which this behavior is observed in bRo5 chemical matter is debated ( Mobitz, 2023 ), accessible conformations of significantly lower polarity than suggested by TPSA values may be required ( Whitty et al, 2016 ; Mobitz, 2023 ). Tight restrictions on hydrogen bonding are suggested ( Doak et al, 2014 ; Matsson et al, 2016 ; Whitty et al, 2016 ; Mobitz, 2023 ; Volak et al, 2023 ).…”

“…Additionally, increased efflux is common in bRo5 ( Doak et al, 2014 ; Matsson et al, 2016 ; Cantrill et al, 2020 ; Cox et al, 2023 ) and PROTAC development space ( Klein et al, 2021 ). Beyond CNS considerations, the combination of differentiated property space (in particular lipophilicity) and pharmacology results in additional considerations around absorption, distribution, metabolism, and excretion (ADME) testing ( Cantrill et al, 2020 ; Pike et al, 2020 ; Apprato et al, 2023 ; Hornberger and Araujo, 2023 ; Volak et al, 2023 ).…”