An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model

Price, Daniel J.; Drewry, David H.; Schaller, Lee T.; Thompson, B.; Reid, Paul R.; Maloney, Patrick; Liang, Xi; Banker, Periette; Buckholz, Richard G.; Selley, Paula K.; McDonald, Octerloney B.; Smith, Jeffery L.; Shearer, Todd; Cox, Richard F.; Williams, Shawn P.; Reid, Robert A.; Tacconi, Stefano; Faggioni, Federico; Piubelli, Chiara; Sartori, Ilaria; Tessari, Michela; Wang, Tony Y.

doi:10.1016/j.bmcl.2018.03.034

Cited by 23 publications

(52 citation statements)

References 14 publications

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“…Price et al demonstrated that replacement of the carboxylic acid group by an amide retained CAMKK2 potency. [89] The authors also demonstrate that the cyclopentyl group occupied a pocket that tolerated alternative substitutions, although no group larger than the cyclopentyl was reported. The unsubstituted phenyl ring could also be functionalized, and there is likely room to grow this into the solvent exposed region where kinases tend to be less highly conserved.…”

Section: Discussionmentioning

confidence: 98%

“…[88] CAMKK2 inhibition has been shown to limit ghrelin-induced food intake in mice. [89] Furthermore, CAMKK2 null mice accumulate less body weight than wild-type mice when fed a high-fat diet, thereby offering protection against diet-induced obesity that promotes NAFLD. [90] In mouse models, treatment with STO-609 improved hepatic steatosis (fatty liver disease) compared to control groups.…”

Section: Camkk2 As a Potential Drug Discovery Targetmentioning

confidence: 99%

“…The scaffolds of CAMKK2 inhibitors (2-6) with structure activity studies described in the literature. [89,126] Price et al identified CAMKK2 inhibitors from a screen of 12,000 ATP-competitive kinase inhibitors and similar pharmacophores. The azaindole and anilino-pyrimidine cores are well documented as Type 1 kinase inhibitors that displace ATP from the hinge region of the enzymes.…”

Section: Figurementioning

confidence: 99%

“…When orally dosed, rats treated with the compound showed a 40% reduction in ghrelin-induced food intake compared to a control group. [89] The 1,2,6-thiadiazin-4-one derivatives identified by Asquith et al represent an unusual class of hinge binders. The compounds were screened against a kinase panel representing the major branches of the kinome.…”

Section: Figurementioning

confidence: 99%

“…cores [89]. In the publication by Asquith et al, 1,2,6-thiadiazin-4-ones (6) derivatives were shown to have only moderate…”

mentioning

confidence: 99%

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In depth analysis of kinase cross screening data to identify CAMKK2 inhibitory scaffolds

O’Byrne

Scott

Pilotte

et al. 2020

Preprint

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The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays a central role in many cell signaling pathways. CAMKK2 activates CAMK1, CAMK4, AMPK, and AKT leading to numerous physiological responses. Deregulation of CAMKK2 is linked to several diseases, suggesting utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work we review the role of CAMKK2 in biology and disease. Through analysis of literature and public databases we have identified starting points for CAMKK2 inhibitor medicinal chemistry campaigns. These starting points provide an opportunity for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.

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Section: Discussionmentioning

confidence: 98%

Section: Camkk2 As a Potential Drug Discovery Targetmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

“…cores [89]. In the publication by Asquith et al, 1,2,6-thiadiazin-4-ones (6) derivatives were shown to have only moderate…”

mentioning

confidence: 99%

See 3 more Smart Citations

In depth analysis of kinase cross screening data to identify CAMKK2 inhibitory scaffolds

O’Byrne

Scott

Pilotte

et al. 2020

Preprint

Self Cite

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Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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14‐3‐3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C‐terminal helices

Petrvalska,

Honzejkova,

Koupilova

et al. 2023

Protein Science

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Ca2+/CaM‐dependent protein kinase kinases 1 and 2 (CaMKK1 and CaMKK2) phosphorylate and enhance the catalytic activity of downstream kinases CaMKI, CaMKIV and protein kinase B. Accordingly, CaMKK1 and CaMKK2 regulate key physiological and pathological processes, such as tumorigenesis, neuronal morphogenesis, synaptic plasticity, transcription factor activation, and cellular energy homeostasis, and promote cell survival. Both CaMKKs are partly inhibited by phosphorylation, which in turn triggers adaptor and scaffolding protein 14‐3‐3 binding. However, 14‐3‐3 binding only significantly affects CaMKK1 function. CaMKK2 activity remains almost unchanged after complex formation for reasons still unclear. Here, we aim at structurally characterizing CaMKK1:14‐3‐3 and CaMKK2:14‐3‐3 complexes by SAXS, H/D exchange coupled to MS, and fluorescence spectroscopy. The results revealed that complex formation suppresses the interaction of both phosphorylated CaMKKs with Ca2+/CaM and affects the structure of their kinase domains and autoinhibitory segments. But these effects are much stronger on CaMKK1 than on CaMKK2 because the CaMKK1:14‐3‐3γ complex has a more compact and rigid structure in which the active site of the kinase domain directly interacts with the last two C‐terminal helices of the 14‐3‐3γ protein, thereby inhibiting CaMKK1. In contrast, the CaMKK2:14‐3‐3 complex has a looser and more flexible structure, so 14‐3‐3 binding only negligibly affects the catalytic activity of CaMKK2. Therefore, Ca2+/CaM binding suppression and the interaction of the kinase active site of CaMKK1 with the last two C‐terminal helices of 14‐3‐3γ protein provide the structural basis for 14‐3‐3‐mediated CaMKK1 inhibition.This article is protected by copyright. All rights reserved.

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An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model

Cited by 23 publications

References 14 publications

In depth analysis of kinase cross screening data to identify CAMKK2 inhibitory scaffolds

In depth analysis of kinase cross screening data to identify CAMKK2 inhibitory scaffolds

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

14‐3‐3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C‐terminal helices

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