Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve Article Swipe

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Sophia M. Min , Frances M. Bashore , Jeffery L. Smith , Tammy M. Havener , Stefanie Howell , Haoxi Li , Rafael M. Couñago , Konstantin I. Popov , Alison D. Axtman ·

YOU? · · 2024 · Open Access · · DOI: https://doi.org/10.26434/chemrxiv-2024-39b71

We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its sub-nanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn’s disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.

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In vivo Biochemical engineering Chemistry Nanotechnology Engineering Biology Materials science Biotechnology

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Type: preprint
Language: en
Landing Page: https://doi.org/10.26434/chemrxiv-2024-39b71
PDF: https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/671284a7cec5d6c14286294b/original/development-of-a-second-generation-in-vivo-chemical-probe-for-pi-kfyve.pdf
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DOI: https://doi.org/10.26434/chemrxiv-2024-39b71

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Title: Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve

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Type: preprint

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Language: en

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Publication year: 2024

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Publication date: 2024-10-21

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Authors: Sophia M. Min, Frances M. Bashore, Jeffery L. Smith, Tammy M. Havener, Stefanie Howell, Haoxi Li, Rafael M. Couñago, Konstantin I. Popov, Alison D. Axtman

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Landing page: https://doi.org/10.26434/chemrxiv-2024-39b71

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Concepts: In vivo, Biochemical engineering, Chemistry, Nanotechnology, Engineering, Biology, Materials science, Biotechnology

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abstract_inverted_index.profiles	54
abstract_inverted_index.revealed	59
abstract_inverted_index.COVID-19,	114
abstract_inverted_index.Crohn’s	112
abstract_inverted_index.analogue,	47
abstract_inverted_index.candidate	89
abstract_inverted_index.compound,	42
abstract_inverted_index.compounds	16, 58
abstract_inverted_index.excellent	36
abstract_inverted_index.half-life	82
abstract_inverted_index.including	109
abstract_inverted_index.optimized	1
abstract_inverted_index.promising	46
abstract_inverted_index.resulting	14
abstract_inverted_index.tolerated	64
abstract_inverted_index.(PIKfyve),	12
abstract_inverted_index.Evaluation	49
abstract_inverted_index.arthritis,	111
abstract_inverted_index.clinically	106
abstract_inverted_index.evaluation	92
abstract_inverted_index.impressive	76
abstract_inverted_index.inhibition	98, 102
abstract_inverted_index.inhibitors	128
abstract_inverted_index.orthogonal	126
abstract_inverted_index.rheumatoid	110
abstract_inverted_index.stability.	24, 132
abstract_inverted_index.supporting	122
abstract_inverted_index.(apilimod),	121
abstract_inverted_index.cell-active	6
abstract_inverted_index.development	124
abstract_inverted_index.indications	108
abstract_inverted_index.kinome-wide	29
abstract_inverted_index.selectivity	30, 38, 77
abstract_inverted_index.confirmation	34
abstract_inverted_index.consequences	95
abstract_inverted_index.demonstrated	21
abstract_inverted_index.investigated	105
abstract_inverted_index.systemically	65
abstract_inverted_index.bioavailable.	68
abstract_inverted_index.sub-nanomolar	72
abstract_inverted_index.SGC-PIKFYVE-1,	13
abstract_inverted_index.pharmacokinetic	52
abstract_inverted_index.phosphatidylinositol-3-phosphate	10
cited_by_percentile_year
countries_distinct_count	2
institutions_distinct_count	9
citation_normalized_percentile.value	0.21375915
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False