DPAP1 Inhibitor | BI-2051

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Target protein: 
DPAP1
Probe Name: 
BI-2051
MOLECULAR WEIGHT [DA]: 
324
In stock: 
839

Chemical structure

Highlights

BI-2051 is a highly selective, soluble and cellular permeable inhibitor of the P. falciparum protease dipeptidyl aminopeptidase 1 (DPAP 1).

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Target information

Dipeptidyl aminopeptidase 1 (DPAP1) is a cysteine exopeptidase expressed in the food vacuoles of the parasite Plasmodium falciparum1.

P. falciparum uses the hemoglobin in the host erythrocytes as a source of amino acids and this catabolism is essential for the intraerythrocytic growth of the parasite. Hemoglobin is taken up by the cytostome and delivered into the food vacuole. In the food vacuole, hemoglobin is degraded by aspartic, cysteine and metalloproteases. DPAP1 catalyzes the final step, the release of small peptides or amino acids from globin-derived oligopeptides1. DPAP1 is therefore a potential target to interfere with the growth of P. falciparum during the erythrocytic phase of its life cycle2.

DPAP1 shows significant sequence homology to the human protease Cathepsin C (CatC).

BI-2051, 3D conformation

BI-2051, 3D conformation

In vitro Activity

BI-2051 displays an IC50 = 0.3 nM in a DPAP1 assay using recombinant protein.

Probe name

BI-2051

MW [Da]

324

DPAP1 (IC50) [nM]a

0.3

Human CatC (IC50) [nM]a

2.691

Human CatK (IC50) [nM]a

4.301

Human CatL (IC50) [nM]a

>100.000

a Assay conditions for the CatC assay are available in the patent WO2014140075. For DPAP1, CatK, and CatL the assay conditions are identical except for the enzyme nature, concentration, buffer and substrates. More detailed experimental conditions can always be obtained via the “Contact us” formular.

  • For DPAP1, the substrate is H-Pro-Arg-AMC
  • For CatC, the substrate is Gly-Arg-AMC
  • For CatL, the substrate is Z-Phe-Arg-AMC
  • For CatK, the substrate is Z-Gly-Pro-Arg-AMC
  • In vitro DMPK and CMC parameters

    BI-2051 is a highly soluble and permeable compound. It has good in vitro PK properties in rats, but displays a weaker microsomal stability in mice.

    Probe name

    BI-2051

    logP

    >70

    Solubility @ pH 6.8 [µg/ml]

    53.7

    CACO permeability @ pH 7.4 [*10-6 cm/s]

    0.45

    CACO efflux ratio

    n.d.

    MDCK permeability Pappa-b/b-a @ 1µM [10-6 cm/s]

    n.d.

    MDCK efflux ratio

    <23 | 40 | 29

    Microsomal stability (human/mouse/rat) [% QH]

    25 | n.d. | n.d.

    Hepatocyte stability @ 5% plasma (human/mouse/rat) [% QH]

    n.d.

    Plasma protein binding (human/mouse/rat) [%]

    59

    hERG [inh. % @ 10 µM]

    n.d.

    CYP 3A4 (IC50) [µM]

    n.d.

    CYP 2C8 (IC50) [µM]

    n.d.

    CYP 2C9 (IC50) [µM]

    n.d.

    CYP 2C19 (IC50) [µM]

    n.d.

    CYP 2D6 (IC50) [µM]

    n.d.

    Selectivity

    BI-2051 is > 8000x selective for P. falciparum DPAP1 versus the homologous human enzymes CatC, CatK and CatL.

    BI-2051

    SELECTIVITY DATA AVILABLE

    Cerep®

    Yes

    Panlabs®

    No

    Invitrogen®

    No

    DiscoverX®

    No

    Dundee

    No

    Download selectivity data: 

    reference molecules

    No reference molecules available.

    Summary

    BI-2051 is a very potent inhibitor of the P. falciparum protease DPAP1. It inhibits recombinant DPAP1 with an IC50 of 0.3 nM and is highly selective versus the homologous human proteases CatC, CatK and CatL (all IC50 > 2500 nM). BI-2051 is highly soluble at pH 2.2, 4.5, 7 has a good cellular permeability and displays good in vitro PK properties in rats. Microsomal stability in mice is weaker than in human and rats.

    Supplementary data

    References

    1. A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation

      Klemba M., Gluzman I., Goldberg D. E.

      Journal of Biological Chemistry 2004, 279, 43000-43007

    2. Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes

      Deu E., Leyva M. J., Albrow V. E., Rice M. J., Ellman J. A.,Bogyo M.

      Chemical & Biology 2010, 27, 808-819.

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