Structure-guided design and characterization of a clickable, covalent PARP16 inhibitor

Abstract

We introduce the first cysteine-targeted covalent PARP inhibitor (DB008), equipped with a clickable alkyne for enhanced PARP family-wide selectivity, and discovered that inhibition of PARP16 prevents auto-aggregation under nutrient stress.

A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells

“…Interest in drugging cytosolic MARTs for therapeutic purposes is growing (Peng et al, 2017; Yoneyama-Hirozane et al, 2017). Efforts are continuing to develop chemical inhibitors of MARTs, including inhibitors of PARP7 (Gozgit et al, 2021; Sanderson et al, 2023), PARP14 (Schenkel et al, 2021), and PARP16 (Bejan et al, 2022). In our studies, treatment with a PARP14 inhibitor (RBN012759) (Schenkel et al, 2021) phenocopied the effects of mutation of the sites of MARylation on RACK1, indicating that many of the effects of the PARP14 inhibitor were mediated through RACK1 MARylation.…”

“…Beyond these drugs, which target nuclear enzymes, there is a growing interest in drugging cytosolic MARTs (Peng et al, 2017; Yoneyama-Hirozane et al, 2017). In fact, a number of academic labs and pharmaceutical companies are developing chemical inhibitors to tap the unexplored therapeutic potential of MARTs, including inhibitors of PARP7 (Gozgit et al, 2021; Sanderson et al, 2023), PARP14 (Schenkel et al, 2021), and PARP16 (Bejan et al, 2022).…”

Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

“…Additional recent examples for such covalent pathfinder probes with potential impact are the GPX4 inhibitor ML210, 53 the PARP16 inhibitor DB008, 54 the UCHL1 inhibitor IMP-1710, 55,56 and the cMyc binder EN4, 57 which provide promising small-molecule entry points into engaging their respective targets (Figure 5). With the successes in targeting cysteine residues, efforts are now underway to covalently target lysine, serine, tyrosine and arginine side chains.…”

“…Additional recent examples for such covalent pathfinder probes with potential impact are the GPX4 inhibitor ML210, the PARP16 inhibitor DB008, the UCHL1 inhibitor IMP-1710, , and the cMyc binder EN4, which provide promising small-molecule entry points into engaging their respective targets (Figure ).…”

Chemical reaction networks based on conjugate additions on β′-substituted Michael acceptors

“…40 Among the large range of additions of different nucleophiles to different acceptors, [40][41][42][43] many of which can also be run with high enantioselectivity, 40,[44][45][46] some of the key transformations are the Michael addition to form carbon-carbon bonds, 47 the Robinson annulation which is one of the key methods to close rings, 48 as well as the thiol-, aza-, and phospha-Michael additions, which enable the formation of carbon-sulfur, carbon-amine, and carbon-phosphorus bonds respectively, commonly applied in material science [49][50][51] and protein functionalisations. [52][53][54][55][56][57][58] Furthermore, nucleophilic conjugate additions are of biological relevance as the involved Michael acceptors possess high bioactivity due to their reactivity towards various nucleophiles, making them good candidates as covalent modifiers, 59 as well as warheads in activity-based probes. 60 Although their sometimes indiscriminate reactivity towards nucleophiles is responsible for the carcinogenicity and toxicity of some Michael acceptors, 61 precise tuning of their reactivity and substituents to precisely fit the pocket of the active sites of a biological target are commonly applied in the process of drug discovery.…”