PF-04929113 (SNX-5422)

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].

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.

A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.[Pubmed:21908572]

Clin Cancer Res. 2011 Nov 1;17(21):6831-9.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. METHODS: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. RESULTS: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m(2) administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. CONCLUSIONS: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.

PF-04929113 (SNX-5422) is a potent and selective HSP90 inhibitor with Kd of 41 nM and induces Her-2 degradation with IC50 of 37 nM. Phase 1/2.

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