Data from Preclinical Characterization of AZD9574, a Blood–Brain Barrier Penetrant Inhibitor of PARP1

• DOI: 10.1158/1078-0432.c.7158229
• Publication Date: 2024-04-01T07:23:45Z
• Authors: Anna D. Staniszewska; Domenic Pilger; Sonja J. Gill; Kunzah Jamal; Natacha Bohin; Sofia Guzzetti; Jacob Gordon; Gregory Hamm; Gill Mundin; Giuditta Illuzzi; Andy Pike; Lisa McWilliams; Gareth Maglennon; Jonathan Rose; Glen Hawthorne; Miguel Cortes Gon...; Christer Halldin; Peter Johnström; Magnus Schou; Susan E. Critchlow; Stephen Fawell; Jeffrey W. Johannes; Elisabetta Leo; Barry R. Davies; Sabina Cosulich; Jann N. Sarkaria; Mark J. O'Connor; Petra Hamerlik
• Keywords: Penetrant (biochemical)

<div>AbstractPurpose:<p>We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models.</p>Experimental Design:<p>AZD9574 was interrogated <i>in vitro</i> for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. <i>In vivo</i> determined using subcutaneous as well intracranial mouse xenograft models. Mouse, rat, monkey were used assess AZD9574 BBB penetration rat models evaluate hematotoxicity monotherapy TMZ combination.</p>Results:<p>AZD9574 demonstrated PARP1-selectivity fluorescence anisotropy, PARylation, trapping assays experiments penetration. showed potent single agent homologous recombination repair deficiency vivo</i>. In an O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT)–methylated orthotopic glioma model, superior extending survival tumor-bearing mice compared alone.</p>Conclusions:<p>The three key features—PARP1 PARP1 profile, high central nervous system molecule—supports development best-in-class PARP treatment primary secondary brain tumors. As documented by studies, shows robust anticancer TMZ. is currently phase I trial (NCT05417594).</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-3571" target="_blank">See related commentary Lynce Lin, p. 1217</a></i></p></div>