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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H22O8
Molecular Weight 414.4061
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PICROPODOPHYLLIN

SMILES

COc1cc(cc(c1OC)OC)[C@]2([H])c3cc4c(cc3[C@@]([H])([C@@]5([H])COC(=O)[C@]52[H])O)OCO4

InChI

InChIKey=YJGVMLPVUAXIQN-HAEOHBJNSA-N
InChI=1S/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19+,20-/m0/s1

HIDE SMILES / InChI

Molecular Formula C22H22O8
Molecular Weight 414.4061
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Picropodophyllin (also known as picropodophyllotoxin (PPP)), an orally active insulin-like growth factor 1 receptor (IGF1R) inhibitor that exhibits no activity at the insulin receptor, FGFR, PDGFR or EGFR. Picropodophyllin possesses antineoplastic activity. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. In addition, it effectively inhibits rhambodmyosarcomas tumor proliferation and metastasis in vitro and in an animal model.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P08069
Gene ID: 3480.0
Gene Symbol: IGF1R
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
448 nM
390 mg single, oral
dose: 390 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
2391 nM
520 mg 2 times / day multiple, oral
dose: 520 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
652 nM
520 mg single, oral
dose: 520 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1783 nM
390 mg 2 times / day multiple, oral
dose: 390 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
12921 nM × h
390 mg single, oral
dose: 390 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
13079 nM × h
520 mg 2 times / day multiple, oral
dose: 520 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
3142 nM × h
520 mg single, oral
dose: 520 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
9982 nM × h
390 mg 2 times / day multiple, oral
dose: 390 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PICROPODOPHYLLIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
930 mg 2 times / day multiple, oral
Highest studied dose
Dose: 930 mg, 2 times / day
Route: oral
Route: multiple
Dose: 930 mg, 2 times / day
Sources:
unhealthy
n = 4
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources:
DLT: Febrile neutropenia...
Dose limiting toxicities:
Febrile neutropenia (2 patients)
Sources:
390 mg 2 times / day multiple, oral (unknown)
RP2D
Dose: 390 mg, 2 times / day
Route: oral
Route: multiple
Dose: 390 mg, 2 times / day
Sources:
unhealthy
n = 5
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
DLT: Febrile neutropenia...
Dose limiting toxicities:
Febrile neutropenia (1 pt)
Sources:
520 mg 2 times / day multiple, oral
Studied dose
Dose: 520 mg, 2 times / day
Route: oral
Route: multiple
Dose: 520 mg, 2 times / day
Sources:
unhealthy
n = 7
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources:
DLT: neutropenia, thrombocytopenia...
Dose limiting toxicities:
neutropenia (29%)
thrombocytopenia (29%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Febrile neutropenia 2 patients
DLT
930 mg 2 times / day multiple, oral
Highest studied dose
Dose: 930 mg, 2 times / day
Route: oral
Route: multiple
Dose: 930 mg, 2 times / day
Sources:
unhealthy
n = 4
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 4
Sources:
Febrile neutropenia 1 pt
DLT
390 mg 2 times / day multiple, oral (unknown)
RP2D
Dose: 390 mg, 2 times / day
Route: oral
Route: multiple
Dose: 390 mg, 2 times / day
Sources:
unhealthy
n = 5
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
neutropenia 29%
DLT
520 mg 2 times / day multiple, oral
Studied dose
Dose: 520 mg, 2 times / day
Route: oral
Route: multiple
Dose: 520 mg, 2 times / day
Sources:
unhealthy
n = 7
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources:
thrombocytopenia 29%
DLT
520 mg 2 times / day multiple, oral
Studied dose
Dose: 520 mg, 2 times / day
Route: oral
Route: multiple
Dose: 520 mg, 2 times / day
Sources:
unhealthy
n = 7
Health Status: unhealthy
Condition: non-small cell lung carcinoma
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources:
PubMed

PubMed

TitleDatePubMed
(-)-Arctigenin as a lead structure for inhibitors of human immunodeficiency virus type-1 integrase.
1996 Jan 5
IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells.
2006 Jan 15
Picropodophyllotoxin or podophyllotoxin does not induce cell death via insulin-like growth factor-I receptor.
2007 Mar 15
Phosphorylation of FOXO3a by PI3K/Akt pathway in HK-2 renal proximal tubular epithelial cells exposed to cadmium.
2013 Dec
Sodium arsenite exposure inhibits AKT and Stat3 activation, suppresses self-renewal and induces apoptotic death of embryonic stem cells.
2013 Feb
Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells.
2014 Aug 14
Patents

Sample Use Guides

In the first phase, 10-20 patients will be enrolled and treated with 300-520 mg BID of AXL1717 (picropodophyllin) for 28 days. The primary endpoint of the first phase is to determine the recommended Phase 2 dose (RP2D) of AXL1717 and to assess the safety and toxicity of AXL1717. The study has a 3+3 design and the first cohort will be treated with 400 mg AXL1717 BID for 28 days repeated in up to 5 cycles.
Route of Administration: Oral
Picropodophyllin (PPP) effectively inhibited human Rhabdomyosarcoma cell proliferation in anchorage dependent assay on plastic dishes. Proliferation potential decreased in a dose-dependent manner (cells were treated with increasing doses of PPP (0–3 μM) and the effects of growth arrest were significant after 72 h of treatment. Effective, the subtoxic concentration was estimated to be 0.1 μM for both RH30 cells and RD treated for 72 h. Similarly, PPP inhibited colony formation on soft agar in an anchorage independent assay. Next, was tested the effect of PPP on cell viability/apoptosis and cell cycle. In this experiment, flow cytometric measurement (FACS-based PI staining and Annexin V binding assay) was used to quantify the extent of apoptosis in the total cell population. 24-h exposure to PPP caused a dose-dependent decrease in number of alive cells and increase in the percentage of late apoptotic cells (FITC+, PI+) beginning from 0.5 μM and higher doses of PPP ≥ 2 μM, lead to massive apoptosis and cell death.
Substance Class Chemical
Created
by admin
on Fri Jun 25 23:28:46 UTC 2021
Edited
by admin
on Fri Jun 25 23:28:46 UTC 2021
Record UNII
0F35AOI227
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PICROPODOPHYLLIN
WHO-DD  
Common Name English
AXL1717
Common Name English
PICROPODOPHYLLIN [WHO-DD]
Common Name English
NSC-36407
Code English
(5R,5AS,8AR,9R)-9-HYDROXY-5-(3,4,5-TRIMETHOXYPHENYL)-5,5A,8A,9-TETRAHYDROFURO(3',4':6,7)NAPHTHO(2,3-D)(1,3)DIOXOL-6(8H)-ONE
Systematic Name English
PODOPHYLLOTOXIN IMPURITY A [EP]
Common Name English
PODOPHYLLOTOXIN PICROPODOPHYLLIN
MI  
Common Name English
PODOPHYLLOTOXIN PICROPODOPHYLLIN [MI]
Common Name English
PICROPODOPHYLLOTOXIN
Common Name English
AXL-1717
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C1331
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
FDA ORPHAN DRUG 593617
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
NCI_THESAURUS C1967
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
EU-Orphan Drug EU/3/17/1904
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
Code System Code Type Description
EPA CompTox
477-47-4
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
MESH
C415032
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
PUBCHEM
72435
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
FDA UNII
0F35AOI227
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
EVMPD
SUB33043
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
MERCK INDEX
M8933
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY Merck Index
DRUG BANK
DB12802
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
CAS
477-47-4
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
ChEMBL
CHEMBL283120
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
NCI_THESAURUS
C87736
Created by admin on Fri Jun 25 23:28:46 UTC 2021 , Edited by admin on Fri Jun 25 23:28:46 UTC 2021
PRIMARY
Related Record Type Details
PARENT -> IMPURITY
CHROMATOGRAPHIC PURITY (HPLC/UV)
EP