The patent application covers Synta's proprietary HDC technology, including composition of matter claims covering over 400 HDC compounds synthesized by Synta to date, methods for identifying therapeutically effective compounds, and methods of use against a wide range of diseases and conditions.
Hsp90 is a chaperone protein required by many cancer cells to maintain the stability and function of numerous proteins that drive cancer cell growth, survival, and metastasis. Small molecule inhibitors of Hsp90, including Synta’s drug candidate ganetespib as well as first-generation inhibitors such as 17-AAG and its derivatives, are retained in tumors for as much as 20 times longer than in blood or normal tissue [1, 2]. These properties are believed to be due to overexpression of an active form of Hsp90 in cancer cells as compared to normal tissues, and have been recently applied for tumor imaging [3, 4].
HDCs are drugs consisting of an Hsp90 inhibitor (targeting moiety) joined to an anti-cancer agent (payload) via a cleavable chemical linker optimized for controlled release of payload drug inside cancer cells. Because HDCs are small molecules, they diffuse into the cell passively, avoiding reliance on cell surface antigens or transporters, as is required by other delivery mechanisms such as antibody-drug conjugates (ADCs).
The longer retention of Hsp90 inhibitors in tumors results in higher concentration and longer duration of active payload drug inside cancer cells than occurs with standard administration of unconjugated chemotherapy or other payloads. This enhanced delivery creates the potential for greater cancer cell killing and reduced side effects.
Synta has developed over 400 HD-Conjugated chemotherapeutics, kinase inhibitors, hormone therapies, immunomodulators, and epigenetic modifiers, creating the potential for next-generation compounds in each of these categories. Examples include HD-Conjugated bendamustine, temozolomide, doxorubicin, 5-FU, pemetrexed, SN-38, topotecan, vorinostat, panobinostat, fulvestrant, abiraterone, lenalidomide, pomalidomide, docetaxel, carboplatin, bortezomib, sunitinib, and sorafenib.
Proof-of-concept has been demonstrated in preclinical models of cancer, showing both improved delivery, including greatly increased concentration and duration of payload in tumors as compared to plasma and normal tissues, as well as significantly improved anti-tumor activity compared to administration of unconjugated payload in animal models of cancer.
“We are excited about realizing the potential of this new class of
anti-cancer therapies,” said
The HDC patent application, PCT/US2013/036783, published as International Patent Application No. WO/2013/158644.
3. G. Chiosis, L. Neckers, ACS chemical biology. 2006;1(5):279-284
Ganetespib, an investigational drug candidate, is a selective inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone which controls the folding and activation of a number of client proteins that drive tumor development and progression. Many solid and hematologic tumors are dependent on Hsp90 client proteins including proteins involved in “oncogene addiction” (ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2); proteins involved in resistance to chemotherapy and radiation therapy (ATR, BCL2, BRCA1/2, CDK1/4, CHK1, survivin, and WEE1); proteins involved in angiogenesis (HIF-1alpha, VEGFR, PDFGR, and VEGF); and proteins involved in metastasis (MET, RAF, AKT, MMPs, HIF-1alpha, and IGF-1R). In preclinical models, inhibition of Hsp90 by ganetespib results in the inactivation, destabilization, and eventual degradation of these cancer-promoting proteins. Ganetespib is being evaluated in trials in lung cancer, breast cancer, and other tumor types. The most common adverse event seen to date has been transient, mild or moderate diarrhea, which has been manageable with standard supportive care. Information on these trials can be found at www.clinicaltrials.gov.
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