LENIOLISIB

LENIOLISIB : Inhibitor of PIK3CD

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 ratings)

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Probe LENIOLISIB is in the process of SERP review.

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Information

PIK3CD

Inhibitor

up to 1 uM

Probe Availability:

In Vitro Validations

Uniprot ID: O00329

Target Class: Kinase

Target SubClass: PI3/PI4

Potency: IC50

Potency Value: 11 nM

Potency Assay: Biochemical assay

PDB ID for probe-target interaction (3D structure): 5O83

Target aliases:

Phosphatidylinositol 4,5-bisphosphate 3-kinase cat ...

DOI Reference: 10.1021/acsmedchemlett.7b00293

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

Selectivity within protein family: PIK3a 244 nM, PIK3b 424 nM, PIK3g 2230 nM. CDZ173 showed no activity up to the highest test concentration when tested against CYP isoform assays (3A3, 2D9, 2D6, 2C9), (26) a panel of ion channels (including hERG) (27) and a protease panel. In a panel of 50 safety related targets (GPCRs, ion channels, transporters), CDZ173 only showed measurable activity for hPDE4D (IC50 = 4.7 μM) and 5HT2B (IC50 = 7.7 μM). Furthermore, CDZ173 was tested against a panel of 442 diverse serine/threonine, tyrosine, and lipid kinases utilizing DiscoverX′ KINOMEscan technology at 10 μM. The only kinase that was inhibited by CDZ173 (in addition to the expected Class I PI3Ks) was RPS6KA5 (76% inhibition, no cellular follow-up as no negative impact on safety/tolerability was anticipated).

Probe Selectivity in Cell:

Selectivity within protein family: PIK3a 1670 nM, PIK3b 2250 nM

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Given the CDZ173 selectivity for PI3K family in the KinomeScan profiling and its superior inhibition of PI3Kdelta in cells (56 nM) compared to the inhibition of PI3Kalpha (1670 nM) and PI3Kbeta (2250 nM), I believe using CDZ173 below 1 micromolar concentration in cells will provide selective targeting of PI3Kdelta. Target engagement (i.e. phosphorylation of Akt) should be evaluated at several CDZ173 concentrations below 1 uM, using hypothesis-relevant cell lines (i.e. not a cell line modified to over-express PI3Kdelta). Given that CDZ173 lacks negative control analogues, data obtained with CDZ173 should be validated with genetic knock-down or knock-out of PI3Kdelta. The proposed in vivo doses appear safe, well tolerated. However, target engagement and selectivity (within the PI3K family) in vivo has not been assessed, hence it is unknown how PI3Kdelta-selective this probe would be in vivo.

(last updated: 7 Jul 2022 )