1382979-44-3 Usage
Description
GDC-0084 is a potent and selective inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), which are key signaling proteins involved in cell growth, proliferation, and survival. It has been developed as a potential therapeutic agent for the treatment of various types of cancer.
Uses
Used in Pharmaceutical Industry:
GDC-0084 is used as an inhibitor of PI3K and mTOR for the development of treatments for brain tumors. It targets the PI3K/AKT/mTOR signaling pathway, which is often dysregulated in cancer cells, leading to uncontrolled cell growth and proliferation. By inhibiting these proteins, GDC-0084 can potentially slow down or stop the growth of cancer cells, making it a promising candidate for cancer therapy.
Additionally, GDC-0084 may have potential applications in other industries, such as in research and development for understanding the role of PI3K and mTOR in various diseases, or in the development of drug delivery systems to improve the bioavailability and efficacy of the compound.
Preparation
Stumpf et al. at Genentech Inc. (Roche group) developed an efficient multikilogram process to synthesize the brain penetrant PI3K inhibitor, GDC‐0084, a potential drug candidate for the treatment of several brain cancers. An efficient Suzuki coupling reaction between a chloropyrimidine and an arylboronic ester using a palladium catalyst at low loading was reported. The optimized conditions were demonstrated on 6.75 kg of a chloropyrimidine intermediate, providing 7.49 kg of crude GDC‐0084 (94% yield, 99.4% HPLC purity). Using the commercially available XPhos Pd G2 catalyst, instead of the usual PdCl2(dppf)·CH2Cl2 catalyst, it was possible to reduce the catalyst loading from 2 to 0.5 mol%. A final scavenging/recrystallization combination from Si‐Thiol (a solid‐supported resin) and acetic acid/water provided the crude GDC‐0084 with the required purity and polymorphic form (off‐white solid, 6.41 kg, 83% yield, 99.7% HPLC purity).
Genentech’s route to GDC‐0084 employing a pivotal Suzuki reaction.
Biological Activity
gdc-0084 is a potent and brain penetrant inhibitor of pi3k and mtor with ki values of 2 nm and 70 nm for pi3kα and mtor, respectively [1].glioblastoma (gbm) is the most common primary brain tumor in adults and aberrant pi3k signaling is associated with more than 80% of cases. the pi3k pathway represents a potential target for the treatment of this disease and the inhibitors would need to freely cross the blood-brain barrier (bbb) [1][2].gdc-0084 is a potent and brain penetrant inhibitor of pi3k and mtor. in vitro kinase assay, gdc-0084 exhibited ki values of 2 nm, 46 nm, 3 nm, 10 nm and 70 nm for pi3kα, pi3kβ, pi3kδ, pi3kγ and mtor, respectively. in five different gbm cell lines, gdc-0084 had antiproliferative activities with ec50 values ranging from 0.3 to 1.1 μm. gdc-0084 has excellent human metabolic stability in microsomal and hepatocyte incubations [1]. in transfected cell lines over-expressing human or mouse p-gp or bcrp, gdc-0084 was a poor substrate of these efflux transporters. in mice brain, gdc-0084 significantly lowered pakt and ps6 levels [2].in rats after a 15 mg/kg dose of gdc-0084, the total brain-to-plasma ratio was 1.9-3.3. in subcutaneous u87 glioblastoma tumor xenograft mice model, gdc-0084 significantly inhibited tumor growth in a dose-dependent way. gdc-0084 also concentration-dependently inhibited pakt [1].[1]. heffron tp1, ndubaku co1, salphati l1, et al. discovery of clinical development candidate gdc-0084, a brain penetrant inhibitor of pi3k and mtor. acs med chem lett. 2016 feb 16;7(4):351-6.[2]. salphati l, alicke b, heffron tp, et al. brain distribution and efficacy of the brain penetrant pi3k inhibitor gdc-0084 in orthotopic mouse models of human glioblastoma. drug metab dispos. 2016 dec;44(12):1881-1889. epub 2016 sep 16.
Check Digit Verification of cas no
The CAS Registry Mumber 1382979-44-3 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,3,8,2,9,7 and 9 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 1382979-44:
(9*1)+(8*3)+(7*8)+(6*2)+(5*9)+(4*7)+(3*9)+(2*4)+(1*4)=213
213 % 10 = 3
So 1382979-44-3 is a valid CAS Registry Number.
1382979-44-3Relevant articles and documents
Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084
Stumpf, Andreas,McClory, Andrew,Yajima, Herbert,Segraves, Nathaniel,Angelaud, Remy,Gosselin, Francis
, p. 751 - 759 (2016/05/19)
An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.
TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Page/Page column 91, (2012/06/30)
Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti- inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions. Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.
