SGC-CAMKK2-1: A Chemical Probe for CAMKK2
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthesis
2.2. Eurofins DiscoverX Broad Kinome Profiling (KINOMEscan™)
2.3. CAMKK2 Enzyme Assay
2.4. NanoBRET Cellular Target Engagement
2.5. In Silico Docking of SGC-CAMKK2-1
2.6. Western Blot Analysis
2.6.1. Prostate Cancer Cellular Screening
2.6.2. Breast Cancer Cellular Screening
2.7. Pharmacokinetic Analysis
2.7.1. Animals
2.7.2. Animal Experiments
2.7.3. Pharmacokinetic (PK) Study of Compound 5 and STO-609 in Mice
3. Results
3.1. CAMKK2 Probe Development Synthesis and Profiling
3.2. Development of a Structurally Related Negative Control
3.3. Molecular Basis for Ligand Binding
3.4. CAMKK2 NanoBRET in Cell Target Engagement
3.5. On-Target Cellular Effect (Western Blot)
3.6. Pharmacokinetic Studies
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Disease | Role of CAMKK2 | Pathway | References |
---|---|---|---|
Bone | |||
Age-associated bone degeneration (ex. osteoporosis) | CAMKK2 inhibition promotes trabecular bone formation | Decrease in CAMKK2 causes an increase in osteoblast/osteoclast ratio 1 | [2,3] |
Fracture Healing | CAMKK2 inhibition accelerates bone healing | Decrease in CAMKK2 causes an increase in Indian Hedgehog Signaling | [4] |
Hematopoiesis | |||
Hematopoietic stem cells (HSC) | CaMKK2 regulates stress response to oxygen | HSC functions | [5] |
Acute radiation syn-drome | CaMKK2 inhibition promote hematopoietic recovery | AMPK/p53 | [6] |
Cancer | |||
Breast cancer | Driver | 1. Myeloid functions | [7] |
2. CAMKK2-AMPK | [8] | ||
3. CAMKK2-FAO | [9] | ||
Chronic lymphocytic leukemia | Prognostic marker | Not determined | [10] |
Diffuse gliomas | Driver and prognostic marker | Promoter hypomethylation-↑CAMKK2 | [11] |
Gastric cancer | Driver | Not determined | [12] |
Hepatic cancer | Driver | CAMKK2-CaMKIV-mTOR | [13] |
Lung cancer | Driver | PLAG-GDH1-aKG-CAMKK2-AMPK | [14] |
Ovarian cancer | Driver | CAMKK2-AKT | [15] |
Prostate cancer | Driver and prognostic marker | 1. AR-CAMKK2-AMPK 2. Triptolide-CAMKK2-AMPK 3. AR-CAMKK2-Lipogenesis | [16,17,18,19,20] |
Pancreatic cancer | CaMKK2/ARHGEF2 | [21] | |
Infectious Disease | |||
Immune response | Immune suppression: 1. macrophage maturation 2. granulocyte differentiation | CAMKK2-AMPK | [8,22,23,24] |
Neuroinflammation | CAMKK2 activation of AMPK reduces LPS mediated neuroinflammation | 1. 3C-CAMKK2-AMPK- PGC1α 2. Telmisartan-CAMKK2- AMPK 3. Chemerin-CAMKK2- AMPK-Nrf2 | [25,26,27] |
Viral infection | Promotes viral replication via diversion of host autophagy | CAMKK2-AMPK-autophagy | [28] |
Metabolic Disease | |||
Diabetes (I and II) | Promotes global glucose intolerance Negative impact on pancreatic β cells | CAMKK2-AMPK | [29] |
Diet-induced obesity | CAMKK2 inhibition decreases appetite and weight gain | CAMKK2-AMPK | [30] |
Nonalcoholic fatty liver disease (NFALD) | CAMKK2 inhibition regresses NFALD | Not determined | [31] |
Heart Disease | |||
Atherosclerosis | CAMKK2 phosphorylation of SIRT1 is atheroprotective | CAMKK2-SIRT1 | [32] |
Hypercholesterolemia (precedes atherosclerosis) | CAMKK2-mediated autophagy protects EPC proliferation | ox-LDL exposure-stored Ca2+ release-CAMKK2-mTOR- autophagy | [33] |
Muscle | |||
Duchenne muscular dystrophy and general muscular injury | CAMKK2 loss promotes muscle regeneration through C2C12 myoblast proliferation and differentiation | 1. CAMKK2-AMPK-cdc2-Tyr15-cell cycle arrest | [34] |
2. CAMKK2-AMPK-PGC1α-repression of differentiation | [34] | ||
Neurological Disorders | |||
Alzheimer’s | Promotes Aβ oligomer synaptotoxicity | CAMKK2-AMPK | [35] |
Memory loss | Involved in long-term memory formation | CAMKK2-CREB | [36,37] |
Anxiety and bipolar disorder | Loss of CAMKK2 activity | CAMKK2 autonomous activity | [38,39] |
Schizophrenia | Loss of CAMKK2 activity | Not determined | [40] |
Epilepsy | Loss of CAMKK2 activity | Not determined | [41] |
Stroke | CAMKK2 loss exacerbates stroke outcomes | 1. CAMKK2-CaMKIV- CREB/Bcl-2 | [42] |
2. CaMKK2-CaMKIV-reduced inflammatory response | [42,43] |
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Wells, C.; Liang, Y.; Pulliam, T.L.; Lin, C.; Awad, D.; Eduful, B.; O’Byrne, S.; Hossain, M.A.; Catta-Preta, C.M.C.; Ramos, P.Z.; et al. SGC-CAMKK2-1: A Chemical Probe for CAMKK2. Cells 2023, 12, 287. https://doi.org/10.3390/cells12020287
Wells C, Liang Y, Pulliam TL, Lin C, Awad D, Eduful B, O’Byrne S, Hossain MA, Catta-Preta CMC, Ramos PZ, et al. SGC-CAMKK2-1: A Chemical Probe for CAMKK2. Cells. 2023; 12(2):287. https://doi.org/10.3390/cells12020287
Chicago/Turabian StyleWells, Carrow, Yi Liang, Thomas L. Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O’Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, and et al. 2023. "SGC-CAMKK2-1: A Chemical Probe for CAMKK2" Cells 12, no. 2: 287. https://doi.org/10.3390/cells12020287