HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors.
The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
David A
DA
Proia
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Donald L
DL
Smith
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Junyi
J
Zhang
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
John-Paul
JP
Jimenez
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Jim
J
Sang
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Luisa Shin
LS
Ogawa
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Manuel
M
Sequeira
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Jaime
J
Acquaviva
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Suqin
S
He
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Chaohua
C
Zhang
NexusPharma Inc., Langhorne, Pennsylvania.
Vladimir
V
Khazak
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Igor
I
Astsaturov
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Takayo
T
Inoue
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Noriaki
N
Tatsuta
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Sami
S
Osman
Synta Pharmaceuticals Corp., Lexington, Massachusetts.
Richard C
RC
Bates
Synta Pharmaceuticals Corp., Lexington, Massachusetts. wying@syntapharma.com dineshc@syntapharma.com.
Dinesh
D
Chimmanamada
Synta Pharmaceuticals Corp., Lexington, Massachusetts. wying@syntapharma.com dineshc@syntapharma.com.
Weiwen
W
Ying
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012118:Resorcinols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D012118:Resorcinols; C533237:STA 9090; C000610389:STA-12-8666; D059004:Topoisomerase I Inhibitors; D014230:Triazoles; D000077146:Irinotecan; D002166:Camptothecin