Optimization of an Imidazo[1,2-<i>a</i>]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with <i>In Vivo</i> Efficacy

McCoull, William; Boyd, Scott; Brown, M.; Coen, Muireann; Collingwood, O.; Davies, Nichola L.; Doherty, Ann; Fairley, Gary; Goldberg, Kristin; Hardaker, Elizabeth; He, Guoqing; Hennessy, Edward J.; Hopcroft, Philip; Hodgson, George; Jackson, Anne; Jiang, Xiefeng; Karmokar, Ankur; Lainé, Anne-Laure; Lindsay, Nicola; Mao, Yumeng; Markandu, Roshini; McMurray, Lindsay; McLean, Neville; Mooney, Lorraine; Musgrove, Helen; Nissink, Johannes W.; Pflug, A.; Reddy, Venkatesh Pilla; Rawlins, Philip; Rivers, Emma; Schimpl, M.; Smith, G. F.; Tentarelli, Sharon; Travers, Jon; Troup, Robert I; Walton, Josephine; Wang, Cheng; Wilkinson, Stephen D.; Williamson, Beth; Winter-Holt, Jon; Yang, Dejian; Zheng, Yuting; Zhu, Qianxiu; Smith, Paul D.

doi:10.1021/acs.jmedchem.1c00920

Cited by 18 publications

(18 citation statements)

References 26 publications

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“…As previously described, our novel imidazo[1,2-a]pyridine dual Mer/Axl type 1½ kinase inhibitor (AZ14145845, (McCoull et al 2021 )) displayed excellent on-target potency (MERTK pIC 50 enzyme 9.0 and Cos-7 cell 7.7, Table 1 ) and activity in a macrophage efferocytosis assay (pIC 50 7.6). In addition, kinome profiling (Thermofisher coverage of 387 kinases at 1 μM) revealed excellent selectivity with > 90% inhibition of MERTK and AXL, and one additional kinase with > 75% inhibition: MAP4K5 (KHS1).…”

Section: Resultsmentioning

confidence: 84%

“…In addition, the choice of a pigmented strain of mice most closely mimics the pigmented human eye, and hence has the greatest translational relevance. Furthermore, our syngeneic MC38 efficacy models also utilized this strain and hence, we had confidence in comparative target engagement across both efficacy and safety models (McCoull et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, our tool compound is well characterized and highly selective, and we identified no off-target risks from broad secondary pharmacology profiling, that could be linked to ocular toxicity and would confound interpretation of this work. Furthermore, we identified target engagement in a range of cell models and dose dependent in vivo efficacy and target engagement in MERTK-dependent mouse models (McCoull et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…We sought to apply a range of state-of-the-art technologies to assess the effect of MERTK inhibition on ocular integrity in a 28 day mouse safety study with a selective tool compound that had demonstrated efficacy in a range of pre-clinical xenograft and immuno-oncology models [e.g., MERTK Ba/F3 efficacy models, syngeneic MC38 model (McCoull et al 2021 )]. Firstly, we confirmed the presence and distribution of compound in the eye and retinal layers using mass spectrometry based multiscale imaging tools.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

et al. 2022

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The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

et al. 2022

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“…pMER ELISA assay was performed in a MER transiently transfected COS-7 cell line as previously described. 22 Data is the mean of at least two independent measurements.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Identification and Strategies to Mitigate High Total Clearance of Benzylamine-Substituted Biphenyl Ring Systems

Winter-Holt

McCoull

2022

Mol. Pharmaceutics

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For most oral small-molecule projects within drug discovery, the extent and duration of the effect are influenced by the total clearance of the compound; hence, designing compounds with low clearance remains a key focus to help enable sufficient protein target engagement. Comprehensive understanding and accurate prediction of animal clearance and pharmacokinetics provides confidence that the same can be observed for human. During a MERTK inhibitor lead optimization project, a series containing a biphenyl ring system with benzylamine meta-substitution on one phenyl and nitrogen inclusion as the meta atom on the other ring demonstrated multiple routes of compound elimination in rats. Here, we describe the identification of a structural pharmacophore involving two key interactions observed for both the MERTK program and an additional internal project. Four strategies to mitigate these clearance liabilities were identified and systematically investigated. We provide evidence that disruption of at least one of the interactions led to a significant reduction in CL that was subsequently predicted from rat hepatocytes using in vitro/in vivo extrapolation and the well-stirred scaling method. These tactics will likely be of general utility to the medicinal chemistry and DMPK community during compound optimization when similar issues are encountered for biphenyl benzylamines.

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Interpretation of multi-task clearance models from molecular images supported by experimental design

Mora¹,

Mogemark²,

Subramanian³

et al. 2022

Artificial Intelligence in the Life Sciences

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Optimization of an Imidazo[1,2-a]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with In Vivo Efficacy

Cited by 18 publications

References 26 publications

Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

Identification and Strategies to Mitigate High Total Clearance of Benzylamine-Substituted Biphenyl Ring Systems

Interpretation of multi-task clearance models from molecular images supported by experimental design

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