677338-12-4 Usage
Description
N-(2,3-Dihydro-7,8-dimethoxyimidazo[1,2-c]quinazolin-5-yl)-3-pyridinecarboxamide, also known as PIK-90, is a potent inhibitor of the phosphoinositide 3-kinase (PI3K) family of enzymes, specifically targeting the α, γ, and δ isoforms with IC50 values of 11 nM, 18 nM, and 58 nM, respectively. It exhibits less potency towards the β isoform, making it a selective inhibitor for the aforementioned isoforms.
Uses
Used in Pharmaceutical Industry:
PIK-90 is utilized as a PI3Kα/γ/δ inhibitor for the development of therapeutic agents targeting various diseases, particularly cancer. Its selective inhibition of these PI3K isoforms allows for the modulation of cellular processes such as cell growth, survival, and metabolism, which are often dysregulated in cancer cells.
Used in Cancer Research:
In the field of cancer research, PIK-90 serves as a valuable tool for studying the role of PI3Kα/γ/δ in tumorigenesis and the underlying mechanisms of cancer progression. Its use in preclinical models helps researchers understand the potential therapeutic benefits and limitations of targeting these specific PI3K isoforms in cancer treatment.
Used in Drug Discovery:
PIK-90 is employed in drug discovery efforts to identify novel compounds with improved potency, selectivity, and pharmacokinetic properties. Its use in high-throughput screening assays and medicinal chemistry optimization processes aids in the development of next-generation PI3K inhibitors with enhanced therapeutic potential.
Used in Combination Therapy:
PIK-90 can be used in combination therapy approaches to enhance the efficacy of existing cancer treatments. By targeting multiple signaling pathways simultaneously, combination therapies have the potential to overcome drug resistance and improve patient outcomes in various cancer types.
In vitro
PIK-90 shows distinct patterns of isoform selectivity to inhibit different subsets of four class I PI3K isoforms. In addition, PIK-90 completely inhibits the fMLP-stimulated phosphorylation of Akt and impairs polarity and chemotaxis in dHL60 cells. PIK-90 exhibits significantly antiproliferative activity by effectively blocking phosphorylation of Akt in six glioma cell lines varying in mutational status at PTEN or p53, including U87 MG, SF188, SF763, LN229, A1207 and LN-Z30 cells. Moreover, PIK-90 induces a modest G0G1 arrest at a concentration (0.5 μM) sufficient to inhibit phosphorylation of Akt substantially. In chronic lymphocytic leukemia (CLL) cells, PIK-90 inhibits chemotaxis to levels that are 57.8% of controls at 1 μM and 56.8% of controls at 10 μM. Consistently, PIK-90 inhibits pseudoemperipolesis to levels that are 74.2% PIK-90 of controls at 1 μM and 57.9% of controls at 10 μM. In addition, PIK-90 also leads to a significant reduction of CLL cell migration into the stromal cell layer and decreases CXCL12-induced actin polymerization.
In vivo
Immediately following insulin treatment, PIK-90 (10 mg/kg) completely protects animals from this insulin-stimulated decline in blood glucose.
Biological Activity
pik-90 is a broad-spectrum pi3k inhibitors that inhibits pi3kα, pi3kγ and pi3kδ with ic50 values of 11, 18 and 58nm, respectively [1].studies showed that pik-90 induced increased levels of secreted ige at 1 μmol/l, while it inhibited ige production at doses of greater than 2 μmol/l [2]. pik-90 has been reported to block akt phosphorylation. pik-90 combined with the cdk2 inhibitor has been demonstrated to induce apoptosis in ln229 ptenwt cells. in addition, pik-90 combined with sirna against both cdk1 and cdk2 has shown to induce cell death, whereas pik-90 combined with sirna against cdk1 or cdk2 had no apoptotic effect [3].
in vivo
pik-90 combined with roscovitine revealed a significant reduction of tumor size in nude mice implanted with gbm43 cells [3].
references
[1] van keymeulen a1, wong k, knight za, govaerts c, hahn km, shokat km, bourne hr. to stabilize neutrophil polarity, pip3 and cdc42 augment rhoa activity at the back as well as signals at the front. j cell biol. 2006 jul 31;174(3):437-45. epub 2006 jul 24.[2] zhang tt1, okkenhaug k, nashed bf, puri kd, knight za, shokat km, vanhaesebroeck b, marshall aj. genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances ige production. j allergy clin immunol. 2008 oct;122(4):811-819.e2.[3] cheng ck1, gustafson wc, charron e, houseman bt, zunder e, goga a, gray ns, pollok b, oakes sa, james cd, shokat km, weiss wa, fan qw. dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. proc natl acad sci u s a. 2012 jul 31;109(31):12722-7.
Check Digit Verification of cas no
The CAS Registry Mumber 677338-12-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,7,7,3,3 and 8 respectively; the second part has 2 digits, 1 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 677338-12:
(8*6)+(7*7)+(6*7)+(5*3)+(4*3)+(3*8)+(2*1)+(1*2)=194
194 % 10 = 4
So 677338-12-4 is a valid CAS Registry Number.
677338-12-4Relevant articles and documents
Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)
Scott, William J.,Hentemann, Martin F.,Rowley, R. Bruce,Bull, Cathy O.,Jenkins, Susan,Bullion, Ann M.,Johnson, Jeffrey,Redman, Anikó,Robbins, Arthur H.,Esler, William,Fracasso, R. Paul,Garrison, Timothy,Hamilton, Mark,Michels, Martin,Wood, Jill E.,Wilkie, Dean P.,Xiao, Hong,Levy, Joan,Stasik, Enrico,Liu, Ningshu,Schaefer, Martina,Brands, Michael,Lefranc, Julien
, p. 1517 - 1530 (2016/08/27)
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.
