apilimod   Click here for help

GtoPdb Ligand ID: 9859

Synonyms: LAM-002A (apilimod dimesylate) | LAM002A | STA 5326 | STA-5326 | STA5326
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Apilimod was originally identified as an inhibitor of IL-12/IL-23 production [12], but the molecular mechanism behind this biological effect was undetermined. Inhibition of IL-12/IL-23 production has application for the treatment Th1-and Th17-mediated immunologic pathologies (which are driven by IL-12 and IL-23 respectively) [11-12]. Apilimod has subsequently been identified as a selective inhibitor of the type III phosphoinostol kinase, PIKfyve [4-5].
We provide structural details for the parent molecule, but some bioactivity data may relate to use of the mesylate salt form as stipulated by the compound's USAN (see PubChem CID 115273300).

PIKfyve has been reported as being required for Ebola virus (EBOV) infection of host cells [9], and indeed apilimod has anti-EBOV activity in vitro. More broad-spectrum antiviral activity against Lassa virus (LASV), Marburg virus (MARV) [8] and SARS-CoV-2 [6,10] is supported in the literature. Activity of PIKfyve is markedly modulated by SARS-CoV-2 infection in vitro, and indicates potential hijacking of phosphatidylinositol enzyme activities by the coronavirus [3]. Pharmacological inhibition of this kinase with apilimod has anti-SARS-CoV-2 activity in two model cell lines, A549-ACE2 cells (IC50 7 nM) and Vero E6 cells (IC50 80 nM), and in human iPSC-derived pneumocyte-like cells . A 2022 publication reports that the in vitro inhibition of coronavirus replication by apilimod is not translated to the same activity in a murine model of COVID-19 [7], and that in fact apilimod worsened symptoms in this model. One explanation for this is that PIKfyve has also been implicated as a key component of antigen presentation by dendritic cells [1]. So in respect of the investigation of apilimod in SARS-CoV-2 infection (NCT04446377), inhibition of antigen presentation, the immune response to new antigens, and T-cell activation, might induce a level of immunosuppression that exacerbates exisiting infection or could increase risk of succumbing to other infections during apilimod treatment [2]. Results from the apilimod clinical trials will be interesting.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 84.76
Molecular weight 418.21
XLogP 5.22
No. Lipinski's rules broken 1
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Canonical SMILES Cc1cccc(c1)C=NNc1nc(OCCc2ccccn2)nc(c1)N1CCOCC1
Isomeric SMILES Cc1cccc(c1)/C=N/Nc1nc(OCCc2ccccn2)nc(c1)N1CCOCC1
InChI InChI=1S/C23H26N6O2/c1-18-5-4-6-19(15-18)17-25-28-21-16-22(29-10-13-30-14-11-29)27-23(26-21)31-12-8-20-7-2-3-9-24-20/h2-7,9,15-17H,8,10-14H2,1H3,(H,26,27,28)/b25-17+
Bioactivity Comments
Apilimod has no inhibitory activity vs. other lipid kinases and protein kinases, including PIP4K, PIP5K, mTOR, PI3K, and PI4K isoforms [4]. It impairs infection by SARS-CoV-2 in vitro with an EC50 of 23 nM [10].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphoinositide kinase, FYVE-type zinc finger containing Hs Inhibitor Inhibition 7.2 pKd - 4
pKd 7.2 (Kd 6.5x10-8 M) [4]
Description: Binding constant for Cy5-apilimod to PIKfyve kinase domain.
phosphoinositide kinase, FYVE-type zinc finger containing Hs Inhibitor Inhibition 7.8 pIC50 - 4
pIC50 7.8 (IC50 1.4x10-8 M) [4]
Description: Effect of apilimod on hPIKfyve kinase activity in vitro measuringPI(3)P conversion to PI(3,5)P2.