Uses

PF 04929113 can be used in pharmacological activity and therapeutic use in therapeutic breast cancer drug target for multiclass comparative virtual screening to identify novel Hsp90 inhibitors. HSP90

Biological Activity

pf-04929113 is an inhibitor of hsp90 [1].pf-04929113 is a water soluble and orally bioavailable prodrug of pf-04928473. it is rapidly absorbed and converted into pf-04928473 after oral administration. in mice bearing bt-474 tumor xenografts, treatment of pf-04928473 causes the degradation of the her2 client protein. and no obvious toxicity is observed when the dose of pf-04928473 is up to 150mg/kg. treatment of 100mg/kg pf-04928473 results in complete tumor growth inhibition and in some mice partial tumor regressions. pf-04928473 also shows significant antitumor activity in mice with h1650 xenografts. in addition, as an inhibitor of hsp90, pf-04928473 is reported to inhibit p-erk and p-akt, decrease cd31+ cells and mvd as well as a have an effect on angiogenesis in vivo [1, 2].

Enzyme inhibitor

This potent and selective HSP90 inhibitor (FW = 521.54 g/mol; CAS 908115-27-5; Solubility: 100 mg/mL DMSO, <1mg/mL H2O), also knownas SNX-5422 and (1R,4R)-4-(2-carbamoyl-5-(6,6-dimethyl-4-oxo-3- (trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)phenylamino)cyclohexyl 2- aminoacetate, targets heat shock protein-90 (Kd = 41 nM) and also inhibits Her-2 degradation (IC50 = 37 nM). PF-04929113 also shows potent antiproliferative activity against a broad range of cancer cell types, e.g. MCF-7 (IC50 =16 nM), SW620 (IC50 =19 nM), K562 (IC50 =23 nM), SK-MEL-5 (IC50 =25 nM), and A375 (IC50 =51 nM). SNX2112 inhibits in vitro proliferation, inducing G2/M arrest, and enhanced cytotoxicity, chemosensitivity, and radiosensitivity between 25 and 250 nM, decreasing expression and/or phosphorylation of EGFR, c-MET, AKT, ERK-1 and -2, IκB kinase, and STAT3, corresponding downstream NFκB, AP-1, and STAT3 reporter genes, and target oncogenes and angiogenic cytokines.

in vivo

target

Hsp90

References

[1] chandarlapaty s, sawai a, ye q, scott a, silinski m, huang k, fadden p, partdrige j, hall s, steed p, norton l, rosen n, solit db. snx2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against her kinase-dependent cancers. clin cancer res. 2008 jan 1;14(1):240-8.
[2] okawa y, hideshima t, steed p, vallet s, hall s, huang k, rice j, barabasz a, foley b, ikeda h, raje n, kiziltepe t, yasui h, enatsu s, anderson kc. snx-2112, a selective hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via akt and erk. blood. 2009 jan 22;113(4):846-55.