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In the context of the UK economy’s slow and unbalanced growth, this paper discusses the degree to which recent Conservative Governments in the UK have moved towards the adoption of a strategic and coherent set of industrial policies to enhance economic performance across the country. It starts by outlining the priorities and principles of new forms of industrial strategy which emphasises the importance of cross-sectoral goals, intensive dialogue between government and the private sector, co-ordination between different policies and levels of government, directions to address societal and environmental challenges and the role of place-based policy making. The paper discusses the degree to which these principles have shaped, or been largely absent from, recent industrial policy development in the UK and particularly the interface between industrial and regional policies. It discusses the May Government’s move to set up an Industrial Strategy with a place ‘pillar’ and the influence of a mission approach. It then reviews the Johnson’s Government’s ‘Plan for Growth’ industrial policy agenda, focussing on the recent Levelling Up White Paper and examines how far and in what ways it has embedded these reforming principles. It finds that despite reflecting some of these principles in its rhetoric, the current government programme has substituted innovation and infrastructure policies for an actual industrial strategy, and continues to rely mainly on a top-down and technologically driven type of approach. The agenda lacks the capacity to deliver its levelling up goals due to inadequate funding, an incomplete devolution agenda and insufficiently developed place-based capacities and policies. Future development needs to move the principles from rhetoric into industrial policy direction and design, and to remedy the continuing lack of local and regional collaboration and co-ordination.

Supplementary Figure from Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper

Supplementary Data from Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper

Purpose:We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination.Experimental Design:AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination.Results:AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response.Conclusions:AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).

Over the past ten years or so, concern has mounted about places in the Global North that have been ‘left behind’ by the growth and prosperity experienced in superstar cities and other wealthy regions. This briefing paper summarises the findings from the first stage of the ‘Beyond Left Behind Places’ project, which involved quantitative analysis of changes experienced by regions across the EU15 over the past four decades and draws out key policy implications.

The recent wave of populism has focused attention on ‘left behind’ places as hotspots of discontent. Seeking to remedy their neglect in urban and regional studies, the aim of this paper is to engage with the problems of ‘left behind’ places and to stimulate fresh thinking about alternative approaches. Reflecting the complex and inter-connected issues facing such places, it argues that a new conception is required to address issues of belonging and attachment. The paper outlines the basis of an expanded neo-endogenous development approach, identifying the foundational economy, income and livelihoods, social infrastructures and social innovation as key policy concerns.

The therapeutic concept of antibody drug conjugates (ADCs) is to selectively target tumour cells with small molecule cytotoxic drugs to maximise cell kill benefit and minimise healthy tissue toxicity.An ADC generally consists of an antibody that targets a protein on the surface of tumour cells chemically linked to a warhead small molecule cytotoxic drug.To deliver the warhead to the tumour cell, the antibody must bind to the target protein and in general be internalised into the cell. Following internalisation, the cytotoxic agent can be released in the endosomal or lysosomal compartment (via different mechanisms). Diffusion or transport out of the endosome or lysosome allows the cytotoxic drug to express its cell killing pharmacology. Alternatively, some ADCs (eg EDB-ADCs) rely on extracellular cleavage releasing membrane permeable warheads.One potentially important aspect of the ADC mechanism is the 'bystander effect' whereby the cytotoxic drug released in the targeted cell can diffuse out of that cell and into other (non-target expressing) tumour cells to exert its cytotoxic effect. This is important as solid tumours tend to be heterogeneous and not all cells in a tumour will express the targeted protein.The combination of large and small molecule aspects in an ADC poses significant challenges to the disposition scientist in describing the ADME properties of the entire molecule.This paper will review the ADC landscape and the ADME properties of successful ADCs, with the aim of outlining best practice and providing a perspective of how the field can further facilitate the discovery and development of these important therapeutic modalities.

The UK’s industrial strategy, with local variants, aims to support manufacturing in ‘traditional industrial regions’ (TIRs). Using novel data for advanced manufacturing (AM) industries over several decades, we examine long-term changes in their geography by regions and local authority districts. These industries have shifted away from large urban regions, and local authority districts in TIRs have lost ground relative to those in other regions, although there are variations between industries. Foreign direct investment has tended to locate in non-TIR locations. AM industries have not shifted decisively towards research-intensive regions. We consider the implications for policy initiatives seeking to spark clusters around innovation districts.

This article articulates the thoughts and responses provoked by the welcome and constructively critical and thoughtful commentaries. They are grouped around the following themes: the purpose of con...

The term “left behind” connotes inequalities in wealth and opportunity, and political disaffection. Although definitional disagreements persist, we propose three key insights to understanding what “left behind” is and why it matters: spatial scale, trajectory, and multidimensionality. Emphasising local and individual experiences, we develop a two-stage approach that interrogates the concept of “left behind”: first, a typology of “left behind” neighbourhoods and, second, a consideration of individual-level “left behind” measures, and how these are associated with our “left behind” geographies. Our findings reveal a local geography of “left behind” in England and highlight the multidimensionality of the phenomenon.

The ongoing Covid-19 crisis and recession represent one of the biggest shocks to the UK manufacturing ecosystem yet, and comes at a time when the ecosystem was already in a worrying situation after decades of deindustrialisation, a decade of austerity and an impending ‘Brexit’. The effects of this shock will also be unevenly felt due to the geography of the UK manufacturing ecosystem, amplifying the need for a successful response to ensure that places are not left (further) behind. This paper assesses the pre-Covid-19 ecosystem to ascertain the areas and industries likely to be particularly impacted by the crisis, and to understand existing issues. These issues are important to consider due to the implications for choosing strategies moving forward, for which two are appraised here. First, the reshoring of supply chains is considered in light of recent government comments, but difficulties in implementation may arise due to the highly fragmented nature of UK policy frameworks. Second, an acceleration of the ‘grand challenges’ approach is likely but limited by issues of connectivity in the ecosystem and small and medium-sized firm disengagement. We suggest that any strategy moving forward must strike a balance between such strategies

Deindustrialization is central to the renewed concern with the social and spatial inequalities and political-economic discontent evident in so-called left behind places in the global North since th...

In the context of debates about (inner-)peripheries, peripheralization and suspended regions, access to service infrastructure and provision is an important aspect that can cause further reduction of the potential of a region. Therefore, it is important to have an indicator for service accessibility that is comparable across different NUTS3 regions regardless of the size or location of the region. In this working paper, we propose to use the population weighted median travel time to the nearest service as indicator. We construct such population weighted median travel times for a number of services of general interest including shops, pharmacies, and schools, based on data from the ESPON PROFECY project. Additionally, we look at how the travel times to different services are correlated with each other at NUTS3 level and how they correlate to population density and to the urban-rural typology of Eurostat.

This paper presents a cluster analysis of structural economic change within NUTS3 regions in the EU15. Based on regional changes in the employment shares of broad sectors since 1980, as well as the degree of initial and current specialisation in each sector, regions are allocated to one of eight clusters via a k-means clustering approach. These clusters are then interpreted in light of current debates about ‘left behind places’. We find that there are several clusters of regions that have experienced less favourable structural change over the past four decades, each with their own set of characteristics.

Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination. Experimental Design: AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination. Results: AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response. Conclusions: AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).

The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)

Engaging the ‘Geographies of Dissociation’ in the spirit of constructive dialogue and debate, this commentary recognizes its contributions and raises issues and questions relating to the potential and perils of pluralism, value, the material and the symbolic, and uneven geographical development and its politics. Building on the claim that pluralism needs to be a means to greater explanation and understanding rather than an end in and of itself, it argues for a more balanced culturally and politically grounded economic geography.

This Special Issue aims to further understanding and explanation of the funding, financing and governing of urban infrastructure amidst its engagements with contemporary financialisation. Drawing upon empirical material from international cases from Europe, North America, Africa and Asia, it identifies critical issues to advance work in this area. These themes concern: the impacts of financialisation upon shifting the definitions and conceptualisations of urban infrastructure; the worth of adopting more actor-oriented and grounded approaches to financialisation; the importance of affording greater recognition to national and local states as the objects and agents of financialising relations, processes and practices; the substance and ramifications of the emergent informalisation of infrastructure policy-making and governance; and, the implications of financialisation for the evolving and uneven landscapes of urban infrastructure provision. The arguments are, first, that how infrastructure is funded, financed and governed is integral to explaining socially and spatially uneven infrastructural provision and its urban development ramifications; and second, the engagements of urban infrastructure with contemporary financialisation have become central in such accounts. Future research avenues are identified. These comprise: identifying exactly how revenues are generated from infrastructure assets; specifying the relations of financialisation with other processes such as ‘assetisation’, ‘marketisation’ and privatisation; extending the geographical and comparative reach of current studies; elaborating the spaces of regulation in negotiating and accommodating infrastructure financialisation; and, scrutinising the roles of decentralised powers and resources in financialising urban infrastructure and exploring its alternatives.

The cell-surface glycoprotein B7-H4 is overexpressed in a range of solid tumors including breast cancer, ovarian serous carcinoma, endometrial carcinoma, and cholangiocarcinoma, yet has limited expression in normal tissue, making it an attractive target for an antibody-drug conjugate (ADC). This presentation describes for the first time the development of AZD8205, a B7-H4 targeted ADC incorporating a novel topoisomerase 1 inhibitor (TOP1i) linker-warhead, AZ’0133 which was designed to exploit the full potential of B7-H4 as an ADC target. Initially, we investigated a series of more than 35 TOP1i compounds as warheads and achieved activity in a clinically relevant nM range. We further optimized the conjugation site and chemistry to reduce the potential for aggregation while maintaining potency, overcoming major synthetic challenges to deliver a robust synthetic route amenable to scale-up. Finally, with a series of optimized linker-warheads, we explored the impact of linker-warhead design on ADC hydrophobicity, stability, efficacy, pharmacokinetics and tolerability culminating in the development of AZD8205. The primary mechanism of action of AZD8205 is intracellular delivery of the TOP1i warhead to B7-H4 positive cells, leading to DNA damage and apoptotic cell death. AZD8205 drove bystander killing of target negative cells in mixed cultures in vitro, which is further supported by robust antitumor activity observed in in vivo studies with patient-derived xenograft (PDX) tumors with heterogeneous target expression, representing multiple tumor indications. In a study of 26 human TNBC PDX tumors, a single IV administration of 3.5 mg/kg AZD8205 provided an overall response rate of 69% (tumor regression of 30% or greater from baseline) and complete responses observed in 9/26 (36%) of models. To understand the biology underlying antitumor response, we conducted a multiparametric analysis including genomics, proteomics and computational pathology and found that deeper antitumor activity was observed in models with elevated B7-H4 expression as well as in models with defects in DNA damage repair (DDR). To further exploit the DNA damage elicited by the TOP1i warhead, we examined combinations of AZD8205 with small molecules, including a novel PARP1 selective inhibitor, in a BRCA wild type MDA-MB-468 model. These data suggest that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase 1 study in patients with advanced solid tumors is currently ongoing (NCT05123482). Citation Format: Krista Kinneer, Niall J. Dickinson, Luke Masterson, Thais Cailleau, Ian Hutchinson, Balakumar Vijayakrishnan, Nazzareno Dimasi, R. James Christie, Mary McFarlane, Kathryn Ball, Arthur Lewis, Sofia Koch, Lee Brown, Yue Huang, Anton I. Rosenbaum, Jiaqi Yuan, Si Mou, Noel R. Monks, Jon Chesebrough, Ravinder Tammali, Judith Anderton, Darrin Sabol, Frances Anne Tosto, Philipp Wortmann, Zachary A. Cooper, Pauline Ryan, John Hood, Carlos Fernandez Teruel, Carlos Serra Traynor, Andy Pike, Michael Davies, Elisabetta Leo, Kimberly Cook, Nadia Luheshi, Philip W. Howard, Puja Sapra. Discovery and first disclosure of AZD8205, a B7-H4-targeted antibody-drug conjugate utilizing a novel topoisomerase I linker-warhead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1765.

PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and PARP1 trapping onto the DNA. All known clinical PARP1 inhibitors bind at the same site at the catalytic center of the enzyme. However, despite this resemblance they show immensely different outcomes in terms of response rate in the clinic due to their varying degree of PARP trapping ability. Moreover, the first-generation PARP inhibitors were not optimized for selectivity across the PARP family potentially driving undesirable side effects, including intestinal toxicity from tankyrase inhibition or hematological toxicity from PARP2 inhibition. There has been strong rationale for the use of PARP inhibitors in neuro-oncology. However, the first-generation PARP inhibitors have limited CNS distribution as these drugs were not designed for brain penetration. Recently AstraZeneca has reported the discovery of AZD5305, a next generation PARP1 selective inhibitor and PARP1-DNA trapper which was not designed with a CNS penetrant profile. Given the unmet need of a brain penetrant PARP1 inhibitor, we set out to identify a highly potent and selective PARP1 inhibitor and trapper with CNS profile. In our next generation PARP1 inhibitor, we sought to retain the profile of AZD5305 and lower the efflux for CNS penetration. Despite the challenge of narrow SAR, we successfully used the structure- and property-based design approach to identify a brain penetrant PARP1 inhibitor and PARP1-DNA trapper. We used multiple medicinal chemistry maneuvers such as masking the hydrogen bond donors and core modifications to lower the efflux in order to achieve brain penetration. Further optimization of the nicotinamide mimetic core for potency and metabolic stability led us to the discovery of AZD9574.AZD9574 shows improved selectivity for PARP1 over PARP2 vs AZD5305 and retains its excellent selectivity over other PARP family members. It has low efflux in Caco2, MDCK-MDR1, and MDCK-MDR1-BCRP permeability assays and it also showed CNS penetration in rat and cynomolgus monkey. AZD9574 has excellent secondary pharmacology and acceptable physicochemical properties and good PK in preclinical species.In vitro, AZD9574 selectively inhibits the growth of BRCAm cell lines. Importantly, AZD9574 showed efficacy in an intracranial BRCA1m MDA-MB-436 xenograft model at doses of 3, 10 and 30 mg/kg QD, significantly extending the survival of tumor-bearing mice compared to vehicle control arm.In summary, AZD9574 is a next generation selective PARP1 inhibitor and trapper with CNS penetration. This profile makes it an ideal candidate for treating CNS malignancies or brain metastases that have a dependence on PARP inhibition either as single agent or in combination with other therapies. Citation Format: Avipsa Ghosh, Sudhir M. Hande, Amber Balazs, Derek Barratt, Sabina Cosulich, Barry Davies, Sébastien Degorce, Kevin Embrey, Sonja Gill, Anders Gunnarsson, Giuditta Illuzzi, Peter Johnström, Jordan Lane, Carrie Larner, Rachel Lawrence, Elisabetta Leo, Andrew Madin, Elizabeth Martin, Lisa McWilliams, Lenka O’Connor, Mark O’Connor, Jonathan Orme, Fiona Pachl, Martin Packer, Andy Pike, Philip Rawlins, Marianne Schimpl, Magnus Schou, Anna Staniszewska, Wenzhan Yang, James Yates, Andrew Zhang, XiaoLa Zheng, Stephen Fawell, Petra Hamerlik, Jeffrey Johannes. Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6302.

The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors in the brain. The current study evaluated the potential of AZD9574, a next generation, PARP1 selective inhibitor/trapper, to penetrate the CNS in cynomolgus monkey, and its occupancy of the PARP1 enzyme, using positron emission tomography (PET). In vitro bidirectional efflux assay data suggested AZD9574 showed minimal substrate potential compared to the clinically approved PARP inhibitors. This was reflected in an increased ratio of unbound brain to unbound plasma concentration (Kpuu) in the rat of ~0.31. Therefore AZD9574 was taken forward into cynomolgus monkey PET studies. Firstly, the Kpuu was determined following dosing of [11C]AZD9574, co-administered with unlabeled drug to minimize the impact of specific binding. The high specific signal observed lead to the development of [11C]AZ3391, a PARP1 selective, CNS penetrant PET tracer, which was subsequently used to directly assess the PARP1 target engagement of AZD9574 in the brain. AZD9574 was found to show a Kpuu in cynomolgus monkeys of 0.79, close to unity with unbound plasma concentrations suggesting minimal CNS restriction. Furthermore, an i.v. infusion dose response study with AZD9574, conducted to examine its ability to block target occupancy by the PET tracer [11C]AZ3391, demonstrated a reduction in [11C]AZ3391 accumulation in whole brain. The resulting calculated occupancy of AZD9574 ranged from 17% for the lowest dose (0.003 mg/kg) to 95% for the highest dose tested (0.05 mg/kg). Comparable reduction in occupancy was seen for peripheral tissue, such as bone marrow, supporting the conclusion that AZD9574 shows minimal CNS restriction. These data show that AZD9574 is the first PARP inhibitor to reach the clinic which combines PARP1 selectivity, trapping and high CNS penetration in a single molecule and supports its development as a potential therapy for the treatment of metastatic disease and primary brain tumors. Citation Format: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng. Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5076.

Positron emission tomography (PET) is a molecular imaging technique used to study the distribution of radiolabeled tracer molecules in vivo in a non-invasive fashion. We here report the discovery and preclinical validation of a novel PET tracer for PARP1. Its exquisite selectivity and high contrast in vivo opens up unique opportunities for exploring target engagement and relationships between drug exposure in plasma and PARP1 occupancy during clinical development of PARP1 inhibitors. AZ3391 was identified as a PET radioligand candidate from our medicinal chemistry program investigating novel PARP1 selective inhibitors and radiolabeled with carbon-11 (t1/2=20.4 min) for a series of in vitro and in vivo imaging experiments. Using in vitro autoradiography, dense binding of [11C]AZ3391 was observed in tissues known to be rich in PARP1 (eg tumour xenograft; NHP and human brain cerebellum). [11C]AZ3391 binding was completely abolished by the inclusion of a high concentration of Olaparib or AZD5305 in the incubate, thus demonstrating specific binding to PARP1 in vitro. Following intravenous injection of [11C]AZ3391 in non-human primates, high binding was observed in organs known to express PARP1, eg brain, spleen and bone marrow. The radioactivity in these organs could be blocked in a dose-dependent manner after pre-treatment with increasing doses of AZD9574 (up to 0.05 mg/kg), thus demonstrating specific binding to PARP1 in vivo. This set of preclinical data supports further development of [11C]AZ3391 as a tool to assess drug induced PARP1 engagement in patients. Citation Format: Peter Johnström, Jeffrey Johannes, Andy Pike, Zsolt Cselényi, Magnus Schou. Discovery and preclinical validation of [11C]AZ3391: A first in class blood-brain barrier permeable, subtype selective PARP-1 PET radioligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5977.