Structure‐Based Design of a Macrocyclic PROTAC

Testa, Andrea; Hughes, Scott J.; Lucas, Xavier; Wright, Jane E.; Ciulli, Alessio

doi:10.1002/ange.201914396

Cited by 24 publications

(22 citation statements)

References 32 publications

(87 reference statements)

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“…Structural information on the ternary complexes between target proteins, PROTACs, and E3 ubiquitin ligases is now beginning to allow rational, structure-based design of PROTACs. 4 Design of PROTACs also requires knowledge about how their structures influence their ADME properties, with cell permeability being required for their mode of action. A few recent studies have begun to provide some, albeit sometimes conflicting, insight into how the ADME properties of PROTACs could be optimized.…”

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confidence: 99%

Solution Conformations Shed Light on PROTAC Cell Permeability

Atilaw

Poongavanam

Nilsson

et al. 2020

ACS Med. Chem. Lett.

123

137

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Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.

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mentioning

confidence: 99%

Solution Conformations Shed Light on PROTAC Cell Permeability

Atilaw

Poongavanam

Nilsson

et al. 2020

ACS Med. Chem. Lett.

123

137

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“…We and others have shown that improved PROTAC-induced degradation of BET protein translates to enhanced effect in the viability of BET-dependent cancer cell lines. 38,69 We therefore moved to evaluate the cytotoxicity of our PROTAC series by assessing the viability of BETsensitive lines MV4;11 (acute myeloid leukemia) (Figure 4D) and 22Rv1 (human prostate carcinoma) (Figure 4E). All PROTACs exhibited a marked antiproliferative effect on each cell line, consistent with their activity as degraders.…”

Section: Improving Protac Permeability Increases Protac Bioactivitymentioning

confidence: 99%

“…This allows us to calculate the cooperativity (α) of ternary complex formation (α = Kd binary / Kd ternary , Figure 5C). 34,59,69,[72][73] Figure 5: Fluorescence polarization (FP) of PROTAC binding. Binary and ternary complex formation FP data for amide (A) and ester (B) PROTACs to VHL alone (diamonds and dashed line) or preincubated Brd4 BD2 with PROTAC to VHL (circles and solid line).…”

Section: Improved Potency Is Due To Improved Permeability Rather Than Improvements To Ternary Complex Formationmentioning

confidence: 99%

Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

Klein

Bond

Craigon

et al. 2021

Preprint

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Bifunctional PROTAC degraders belong to "beyond Rule of 5" chemical space, and criteria for predicting their drug-like properties are underdeveloped. PROTAC components are often combined via late-stage amide couplings, due to the reliability and robustness of amide bond formation. Amides, however, can give rise to low cellular permeability and poor ADME properties. We hypothesized that a bioisosteric replacement of an amide with a less polar ester could lead to improvements in both physicochemical properties and bioactivity. Using a library of model compounds, bearing either amides or esters at various linker-warhead junctions, we identify parameters for optimal compound lipophilicity and permeability. We next applied these learnings to design a set of novel amide-to-ester substituted, VHL-based BET degraders with increased permeability. Our ester-PROTACs remarkably retained intracellular stability, were overall more potent degraders than their amide counterparts and showed an earlier onset of the hook effect. These enhanced cellular features were found to be driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution therefore provides a simple and practical strategy to enhance PROTAC permeability and degradation performance. Such approach could prove equally beneficial to other classes of beyond Ro5 molecules. Introduction:Targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are becoming a widespread source of chemical probes and lead compounds that degrade rather than inhibit target proteins, providing a different drug modality with potential to expand the "druggable" proteome. [1][2][3][4][5][6][7] These chimeric molecules typically contain a protein-of-interest (POI)targeting ligand (or warhead) and a ligand which binds to an E3 ligase, connected by a linker. 8-10 PROTAC-induced ternary complexes between the POI and E3 ligase are required for polyubiquitination and targeted degradation of the POI. 11 PROTACs do not require full target occupancy, because a single PROTAC molecule can induce degradation of more than one target protein molecule over time, thereby acting catalytically at sub-stoichiometric target occupancy. These distinct features of PROTACs mode of action have been shown to result in increased target selectivity, higher potencies, and fewer off-target effects compared to small molecule inhibitors. 10, 12-14 Furthermore, unlike small molecule inhibitors, PROTACs can bind the target at any position, including non-functional binding sites. 10,15 Notably, PROTACs have shown to be developable for use in humans, with several compounds reaching the clinic, including ARV-110 and ARV-471 that have recently progressed into Phase II clinical trials for prostate and breast cancer, respectively, demonstrating both safety and efficacy in patients. [16][17][18] While PROTACs harbor several advantages as a new modality within drug discovery, their bifunctional nature and chemical composition mean th...

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“…Very recently, a macrocyclic protac has been designed as a conformationally restricted analog of the BET degrader MZ1 [ 168 ]. As it is common in classical drug design, the use of this conformationally restricted analog leads to a more selective degrader with a cellular activity comparable to that of the parent flexible protac.…”

Section: Miscellaneous Protacsmentioning

confidence: 99%

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

2020

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The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.

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Structure‐Based Design of a Macrocyclic PROTAC

Cited by 24 publications

References 32 publications

Solution Conformations Shed Light on PROTAC Cell Permeability

Solution Conformations Shed Light on PROTAC Cell Permeability

Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

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