ALVOCIDIB HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H20ClNO5.ClH
Molecular Weight	438.301
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CN1CC[C@@H]([C@H](O)C1)C2=C(O)C=C(O)C3=C2OC(=CC3=O)C4=C(Cl)C=CC=C4

InChI

InChIKey=LGMSNQNWOCSPIK-LWHGMNCYSA-N

InChI=1S/C21H20ClNO5.ClH/c1-23-7-6-12(17(27)10-23)19-14(24)8-15(25)20-16(26)9-18(28-21(19)20)11-4-2-3-5-13(11)22;/h2-5,8-9,12,17,24-25,27H,6-7,10H2,1H3;1H/t12-,17+;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27118540
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT00020332 | https://clinicaltrials.gov/ct2/show/NCT00020189 | https://clinicaltrials.gov/ct2/show/NCT00464633 | https://clinicaltrials.gov/ct2/show/NCT00445341

Alvocidib (also known as Flavopiridol or HMR-1275) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development for the treatment of acute myeloid leukemia, by Tolero Pharmaceuticals, Inc. As a broad spectrum CDK inhibitor, Alvocidib can inhibit cell cycle progression in either G1 or G2 and induces G1 arrest in either MCF-7 or MDA-MB-468 cells by inhibition of the CDK4 or CDK2 kinase activity. Alvocidib exhibits potent cytotoxicity against a wide variety of tumor cell lines (LNCAP, HCT116, A2780, K562, PC3, and Mia PaCa-2) with IC50 values ranging from 16 nM for LNCAP to 130 nM for K562. Administration of Alvocidib at 7.5 mg/kg for 7 days displays slight antitumor activity against P388 murine leukemia, and active against the human A2780 ovarian carcinoma implanted sc in nude mice). Alvocidib treatment at 1-2.5 mg/kg for 10 days significantly suppresses collagen-induced arthritis in mice in a dose-dependent manner, by inhibiting synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII are maintained. Tolero Pharmaceuticals Inc. announced that the FDA has granted orphan drug designation for Alvocidib, its cyclin-dependent kinase small molecule inhibitor, for the treatment of patients with acute myeloid leukemia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cyclin-dependent kinase 4 22 Target ID: CHEMBL331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378	Inhibitor 8297	3.3 nM [Kd]
Cyclin-dependent kinase 9 19 Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23252711	Inhibitor 8297	3.0 nM [Ki]
Cyclin-dependent kinase-like 5 3 Target ID: CHEMBL1163112 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378	Inhibitor 8297	7.1 nM [Kd]
Serine/threonine-protein kinase ICK 3 Target ID: CHEMBL1163126 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378	Inhibitor 8297	0.69 nM [Kd]

Conditions

Condition	Modality	Highest Phase	Product
Head and neck cancer 50 Sources: https://clinicaltrials.gov/ct2/show/NCT00020189	Primary	Phase II 1132	Unknown Approved Use Unknown
Thromboembolism 8 Sources: https://clinicaltrials.gov/ct2/show/NCT00020189	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/NCT00020332	Primary	Phase II 1132	Unknown Approved Use Unknown
Adult acute megakaryoblastic leukemia 3 Sources: https://clinicaltrials.gov/ct2/show/NCT00634244	Primary	Phase II 1132	Unknown Approved Use Unknown
Chronic lymphocytic leukemia 59 Sources: https://clinicaltrials.gov/ct2/show/NCT00464633	Primary	Phase II 1132	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP1 106	OATP2B1 104 UGT1A3 422 UGT2B4 249 UGT2B28 63 UGT1A4 347 P-gp 1537 UGT2B7 389 UGT1A7 236 OATP1B1 406 UGT2B10 127 UGT1A1 418 UGT1A8 283 BCRP 561 UGT1A9 380 MRP1 107 UGT2B11 3 UGT1A10 291 OATP1B3 350 UGT2B15 203 UGT1A5 55 UGT1A6 307 UGT2B17 213

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10496352/	yes

Drug as victim

Target	Modality	Activity
UGT1A9 380	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	major [Km 37 uM]
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
UGT1A10 291	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
UGT1A3 422	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
UGT1A4 347	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
UGT1A7 236	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
UGT1A8 283	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	minor
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12960118/ \| https://pubmed.ncbi.nlm.nih.gov/11205902/	no
UGT1A5 55	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT1A6 307	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B10 127	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B11 3	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B15 203	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B17 213	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B28 63	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B4 249	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
UGT2B7 389	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12069159/	no
OATP2B1 104	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25351763/	yes [Km 175 uM]
OATP1B1 406	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25351763/	yes [Km 66 uM]
OATP1B3 350	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25351763/	yes [Km 66.8 uM]
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11205902/	yes
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11205902/ \| https://pubmed.ncbi.nlm.nih.gov/10496352/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY116199	https://www.001chemical.com/chem/search?q=DY116199
1PlusChem LLC	1P001EGY	https://www.1pchem.com/search?query=1P001EGY
1PlusChem LLC	1P0038M1	https://www.1pchem.com/search?query=1P0038M1
AChemBlock	P50930	http://www.achemblock.com/catalogsearch/result/?q=P50930
AK Scientific	2106AH	https://aksci.com/item_detail.php?cat=2106AH
Ambeed	A180731	http://www.ambeed.com/search/Search.html?keyword=A180731
Apollo Scientific	BIA8419	http://www.apolloscientific.co.uk/chemical_results.php?qstext=BIA8419&product_group=%25&search_fieldname=header_search
AstaTech	44223	http://astatechinc.com/CPSResult.php?CRNO=44223
AstaTech	C72284	http://astatechinc.com/CPSResult.php?CRNO=C72284
BLD Pharm	BD130402	http://www.bldpharm.com/search/Search.html?keyword=BD130402
BLD Pharm	BD130403	http://www.bldpharm.com/search/Search.html?keyword=BD130403
BioSynth	J-500011	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-500011
Capot Chemical	22427	https://www.capotchem.com/search.do?q=22427
Cayman Chemical	10009197	http://www.caymanchem.com/app/template/Product.vm/catalog/10009197
Chem Scene	CS-0018	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0018
Chem Scene	CS-0306	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0306
ChemShuttle	111849	https://www.chemshuttle.com/catalogsearch/result/?q=111849
ChemShuttle	112400	https://www.chemshuttle.com/catalogsearch/result/?q=112400
Hairui	HR110880	http://www.hairuichem.com/en/product/search.do?q=HR110880
Hairui	HR134920	http://www.hairuichem.com/en/product/search.do?q=HR134920
KeyOrganics	AS-58704	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-58704
KeyOrganics	AS-74761	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-74761
Matrix Scientific	132605	http://www.matrixscientific.com/132605.html
Matrix Scientific	147197	http://www.matrixscientific.com/147197.html
MedChem Express	HY-10005	https://www.medchemexpress.com/search.html?q=HY-10005&ft=&fa=&fp=
MedChem Express	HY-10006	https://www.medchemexpress.com/search.html?q=HY-10006&ft=&fa=&fp=
MolPort	MolPort-006-169-102	https://www.molport.com/shop/molecule-link/MolPort-006-169-102
MolPort	MolPort-006-394-122	https://www.molport.com/shop/molecule-link/MolPort-006-394-122
MolPort	MolPort-039-139-196	https://www.molport.com/shop/molecule-link/MolPort-039-139-196
Molcore	MC116199	http://www.molcore.com/CatMC116199.html
Molnova	M11289	https://www.molnova.com/en/serch-list.html?keywords=M11289
Molnova	M11992	https://www.molnova.com/en/serch-list.html?keywords=M11992
MuseChem	I001773	https://www.musechem.com/product/I001773.html
MuseChem	I001813	https://www.musechem.com/product/I001813.html
Selleck Chemicals	S2679	http://www.selleckchem.com/search.html?searchDTO.searchParam=S2679
ShangHai Biochempartner	BCP000467	http://www.biochempartner.com/search_BCP000467
TargetMol	T2615	https://www.targetmol.com/search?keyword=T2615
TargetMol	T6837	https://www.targetmol.com/search?keyword=T6837
Tocris	3094	https://www.tocris.com/search.php?Type=QuickSearch&Value=3094
Toronto Research Chemicals	C181227	https://www.trc-canada.com/product-detail/?CatNum=C181227
Toronto Research Chemicals	F373000	https://www.trc-canada.com/product-detail/?CatNum=F373000
W&J PharmaChem	RT-	http://wjpharmachem.com/new/searcht.php?keyword=RT-
eMolecules	195179259	https://orderbb.emolecules.com/search/#?query=195179259
eMolecules	195315725	https://orderbb.emolecules.com/search/#?query=195315725
eMolecules	300450414	https://orderbb.emolecules.com/search/#?query=300450414
eMolecules	32176532	https://orderbb.emolecules.com/search/#?query=32176532
eMolecules	37153211	https://orderbb.emolecules.com/search/#?query=37153211
eNovation Chemicals	D372517	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372517&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D395215	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395215&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2051857153	https://mcule.com/MCULE-2051857153/
mcule	MCULE-2249432897	https://mcule.com/MCULE-2249432897/
mcule	MCULE-7025192771	https://mcule.com/MCULE-7025192771/
mcule	MCULE-9910962066	https://mcule.com/MCULE-9910962066/

PubMed

Title	Date	PubMed
Perspectives for cancer therapies with cdk2 inhibitors.	2001 Dec	12030783
Cytotoxic agents in the era of molecular targets and genomics.	2002	12165653
The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01.	2002	12165651
Finding the needle in the haystack: why high-throughput screening is good for your health.	2002	12100740
Highlights in the development of new antiviral agents.	2002 Apr	12370077
Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma.	2002 Apr	12153166
Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol.	2002 Apr 26	12054639
Hematologic malignancies: new developments and future treatments.	2002 Aug	12170431
Progress toward the development of agents to modulate the cell cycle.	2002 Aug	12133723
Cyclin-dependent kinases as cellular targets for antiviral drugs.	2002 Dec	12460995
Pharmacological treatments for prostate cancer.	2002 Dec	12457434
Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol.	2002 Dec	12451473
New insights in the transcriptional activity and coregulator molecules in the arterial wall.	2002 Dec	12419552
Activation of the Rb/E2F1 pathway by the nonproliferative p38 MAPK during Fas (APO1/CD95)-mediated neuronal apoptosis.	2002 Dec 13	12351630
The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells.	2002 Feb	12467221
Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signaling pathways.	2002 Jul	12479366
Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA).	2002 Jul	12094258
Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells.	2002 Jul 15	12124325
Targeting the cell cycle for cancer therapy.	2002 Jul 15	12107831
New developments in anti-HIV chemotherapy.	2002 Jul 18	12084468
Role reversal for anticancer agents.	2002 Jul-Aug	12432260
Flavopiridol inversely affects p21(WAF1/CIP1) and p53 and protects p21-sensitive cells from paclitaxel.	2002 Jul-Aug	12432259
[Report on 93rd AACR].	2002 Jul-Aug	12206987
ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin.	2002 Jul-Aug	12174876
Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy.	2002 Jun	12138401
Synergistic induction of apoptosis in human myeloid leukemia cells by phorbol 12-myristate 13-acetate and flavopiridol proceeds via activation of both the intrinsic and tumor necrosis factor-mediated extrinsic cell death pathways.	2002 Jun	12021392
Flavopiridol inhibits vascular endothelial growth factor production induced by hypoxia or picolinic acid in human neuroblastoma.	2002 Jun 10	12115498
Gene expression profile of HIV-1 Tat expressing cells: a close interplay between proliferative and differentiation signals.	2002 Jun 10	12069692
CDK inhibitors: cell cycle arrest versus apoptosis.	2002 Mar-Apr	12429920
Loss of the Bcl-2 phosphorylation loop domain is required to protect human myeloid leukemia cells from flavopiridol-mediated mitochondrial damage and apoptosis.	2002 Mar-Apr	12170773
In vitro characterization of hepatic flavopiridol metabolism using human liver microsomes and recombinant UGT enzymes.	2002 May	12069159
Evidence for CRK3 participation in the cell division cycle of Trypanosoma cruzi.	2002 May	12034456
Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development.	2002 May	11978170
Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity.	2002 May	11961048
The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1.	2002 Nov	12429644
New anti-HIV agents and targets.	2002 Nov	12369088
Conversion of drug-induced differentiation to apoptosis by pharmacologic cyclin-dependent kinase inhibitors.	2002 Nov-Dec	12548009
Cyclin-dependent kinases as new targets for the prevention and treatment of cancer.	2002 Oct	12512390
Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms.	2002 Oct 1	12351605
Clinical trials referral resource. Flavopiridol.	2002 Sep	12380947
Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells.	2002 Sep	12231544
A high-performance liquid chromatography method using ultraviolet detection for the quantitation of flavopiridol from human plasma.	2002 Sep	12228893
HIV-1 expression induces cyclin D1 expression and pRb phosphorylation in infected podocytes: cell-cycle mechanisms contributing to the proliferative phenotype in HIV-associated nephropathy.	2002 Sep 19	12241561
Signal transduction--directed cancer treatments.	2003	12195027
Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial.	2003 Jan	12538483
Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol.	2003 Jan	12533676
Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1.	2003 Jan	12533675
Flavopiridol, a cyclin dependent kinase (CDK) inhibitor, induces apoptosis by regulating Bcl-x in oral cancer cells.	2003 Jan	12457721
Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.	2003 Jan 1	12517802
Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis.	2003 Jan 1	12517783

Patents

Sample Use Guides

In Vivo Use Guide

30 mg/m2 as a 30-minute intravenous (IV) infusion followed by 30 mg/m2 as a 4-hour continuous infusion. Cycles with 4-week treatment with alvocidib followed by 2-week rest period for up to a maximum of 6 cycles

Route of Administration: Intravenous

In Vitro Use Guide

Skov-3 and BG-1 human ovarian cancer cells were used for activity evaluation. Cells (104/ml) were distributed into 96 well plates (“Greiner”, Frickenhausen, Germany) and allowed to adhere for 24 h. Medium was replaced by fresh medium containing vehicle or treatment reagents (Alvocidib 0.01, 0.1, 1, 10 ,100, 100 nM). After the indicated treatment period, cells were fixed by adding 10% glutamatealdehyde (“Merck”, Darmstadt, Germany) solution and stained by 0.05% crystal violet (“Sigma”) in 25% methanol. Following washing three times with double distilled water, cell bound crystal violet was dissolved in 0.1 M sodium citrate and measured at 560 nm (“ELISA Reader, Tecan”, Grödig, Austria). Experiments repeated in triplicate.

Name

Type

Language

ALVOCIDIB HYDROCHLORIDE

Official Name

English

(-)-CIS-2-(2-CHLOROPHENYL)-5,7-DIHYDROXY-8-(3-HYDROXY-1-METHYLPIPERIDIN-4-YL)-4H-1-BENZOPYRAN-4-ONE HYDROCHLORIDE

Systematic Name

English

HMR-1275

Code

English

ALVOCIDIB HYDROCHLORIDE [MART.]

Common Name

English

FLAVOPIRIDOL HYDROCHLORIDE [MI]

Common Name

English

L-868275

Code

English

ALVOCIDIB HYDROCHLORIDE [USAN]

Common Name

English

4H-1-BENZOPYRAN-4-ONE, 2-(2-CHLOROPHENYL)-5,7-DIHYDROXY-8-((3R,4S)-3-HYDROXY-1-METHYL-4-PIPERIDINYL)-, HYDROCHLORIDE, REL-(-)-

Systematic Name

English

MDL 107,826A

Code

English

Alvocidib hydrochloride [WHO-DD]

Common Name

English

MDL-107826A

Code

English

HL-275

Code

English

HMR 1275

Code

English

NSC-649890

Code

English

L-86-8275

Code

English

FLAVOPIRIDOL HYDROCHLORIDE

Common Name

English

4H-1-BENZOPYRAN-4-ONE, 2-(2-CHLOROPHENYL)-5,7-DIHYDROXY-8-((3S,4R)-3-HYDROXY-1-METHYL-4-PIPERIDINYL)-, HYDROCHLORIDE (1:1)

Systematic Name

English

HL 275

Code

English

L 86 8275

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C2185