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SNX-5422 Overview SNX-5422 is our first Heat Shock Protein 90 (Hsp90) inhibitor candidate. SNX-5422 was discovered, designed and synthesized by Serenex scientists using our core technology. In pre-clinical studies, SNX-5422 has high oral bioavailability in all species tested and has demonstrated significant in vivo efficacy across a broad spectrum of tumor types, including refractory breast cancer, prostate, colon and melanoma. SNX-5422 potency and tolerability exceed that of current clinical compounds derived from the natural product geldanamycin (17-AAG and 17-DMAG and CNF-1010). As an oral formulation that demonstrates strong efficacy and tolerability, SNX-5422 is positioned as a breakthrough therapy with broad applicability across a wide range of cancers. SNX-5422 is currently in phase 1. Pharmaceutical properties SNX-5422 exhibits favorable pharmaceutical attributes including: - Synthetic low molecular weight molecule (rule of 5 compliant)
- Water-soluble (suitable for oral or i.v. dosing)
- Highly selective
- No significant inhibition of key P450 isozymes
- Very rapid conversion to the active agent SNX-2112 in vivo
In addition, the entire extensive SAR library of Serenex's Hsp90 inhibitors is based around a completely novel chemical scaffold unrelated to all previously published Hsp90 inhibitors and is covered by multiple patents. Biological Activity SNX-2112, the active agent of SNX-5422, is a direct, potent inhibitor of Hsp90 across a broad range of human cancer cell lines and causes degradation of important Hsp90 client proteins including HER2, AKT and ERK. Pre-clinical studies using SNX-5422 have demonstrated: - Potent anti-proliferative responses: low nM inhibiton in multiple human cancer cells
- Excellent oral bioavailability and PK properties
- Excellent tolerability in rodent and dog studies
- Significant oral efficacy in xenograft models (colon, breast and prostate) as a single agent and in combination with other cytotoxic and targeted agents
- Preferential accumulation in tumors to concentrations over 10-fold higher than in other tissues. Tumor apoptosis was observed in vivo
The following xenograft studies using human tumors are examples of profound inhibition of tumor growth using SNX-5422 as a single agent and in combination with targeted agents: 
 SNX-5422 and other Hsp90 inhibitors With the exception of Serenex’s family of small molecule Hsp90 inhibitors, all current Hsp90 inhibitors in the public domain have been derived from natural product scaffolds. Working with natural products is challenging and it has proved difficult to develop suitable drug-like properties and selectivity from these derivatives. In contrast, SNX-5422 exhibits a superior pharmacological profile and lacks the quinione functionality that is believed to be associated with natural product-related hepatotoxicity. SNX-5422's superior pharmacological profile includes: - Convenient oral dosing
- Superior efficacy in vivo
- Higher maximum tolerated dose (MTD) and a wider therapeutic window
- Increased potency on a key HSP90-dependent pathway, the anti-apoptotic Akt pathway
SNX-5422 clinical trials SNX-5422 is currently in phase 1 clinical trials.
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