MAC glucuronide α-hydroxy lactone-linked SN-38 - CAS 2246380-70-9

MAC glucuronide α-hydroxy lactone-linked SN-38 - CAS 2246380-70-9 Catalog number: BADC-00667

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MAC glucuronide α-hydroxy lactone-linked SN-38 (Topoisomerase I inhibitor) is a stabilized lactone MAC glucuronide α-hydroxy lactone-linked SN-38 drug linker. MAC glucuronide α-hydroxy lactone-linked SN-38 is cytotoxic across L540cy cells and Ramos cells with IC50 values of 99 and 105 ng/mL, respectively.

Category
ADCs Cytotoxin
Product Name
MAC glucuronide α-hydroxy lactone-linked SN-38
CAS
2246380-70-9
Catalog Number
BADC-00667
Molecular Formula
C50H54N6O20S
Molecular Weight
1091.06
MAC glucuronide α-hydroxy lactone-linked SN-38

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Description
MAC glucuronide α-hydroxy lactone-linked SN-38 (Topoisomerase I inhibitor) is a stabilized lactone MAC glucuronide α-hydroxy lactone-linked SN-38 drug linker. MAC glucuronide α-hydroxy lactone-linked SN-38 is cytotoxic across L540cy cells and Ramos cells with IC50 values of 99 and 105 ng/mL, respectively.
Canonical SMILES
O=C([C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC2=CC=C(COC(N(CO[C@](C3=C(CO4)C(N5CC6=C(CC)C7=CC(O)=CC=C7N=C6C5=C3)=O)(CC)C4=O)CCS(=O)(C)=O)=O)C=C2NC(CN(C)C(CCN8C(C=CC8=O)=O)=O)=O)O1)O
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1.Lactone Stabilization is Not a Necessary Feature for Antibody Conjugates of Camptothecins
Lau UY, Benoit LT, Stevens NS, Emmerton KK, Zaval M, Cochran JH, Senter PD
Camptothecins exist in a pH-dependent equilibrium between the active, closed lactone and the inactive open-carboxylate forms. Several previous reports underscore the need for lactone stabilization in generating improved camptothecins, and indeed, such designs have been incorporated into antibody-drug conjugates containing this drug. Here, we demonstrate that lactone stabilization is not necessary for camptothecin-based ADC efficacy. We synthesized and evaluated camptothecin SN-38 drug linkers that differed with respect to lactone stability and released SN-38 or the hydrolyzed open-lactone form upon cleavage from the antibody carrier. An α-hydroxy lactone-linked SN-38 drug linker preserved the closed-lactone ring structure, while the phenol-linked version allowed conversion between the closed-lactone and open-carboxylate structures. The in vitro cytotoxicity, pharmacokinetic properties, and in vivo efficacy in the L540cy Hodgkin's lymphoma model of the corresponding ADCs were found to be indistinguishable, leading us to conclude that camptothecin-based antibody-drug conjugates possess pronounced activity regardless of the lactone state of the bound drug. This is most likely a result of ADC processing within acidic intracellular vesicles, delivering camptothecin in its active closed-lactone form.
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