Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity

Dahui Zhou; Jeffrey Casavant; Edmund I. Graziani; Haiyin He; Jeffrey Janso; Frank Loganzo; Sylvia Musto; Nathan Tumey; Christopher J. O'Donnell; Russell Dushin

doi:10.1016/j.bmcl.2019.01.009

Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity

Dahui Zhou
, Jeffrey Casavant
, Edmund I. Graziani
, Haiyin He
, Jeffrey Janso
, Frank Loganzo
, Sylvia Musto
, Nathan Tumey
, Christopher J. O'Donnell
, Russell Dushin

Pharmaceutical Sciences

Binghamton University

Pfizer

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.

Original language	English
Pages (from-to)	943-947
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2019.01.009
State	Published - Apr 1 2019

Keywords

ADC
Antitumor
HER2-expressing tumor cell lines
Neolymphostin
PIKK inhibitor
Trastuzumab conjugates

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10.1016/j.bmcl.2019.01.009

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title = "Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity",

abstract = "Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.",

keywords = "ADC, Antitumor, HER2-expressing tumor cell lines, Neolymphostin, PIKK inhibitor, Trastuzumab conjugates",

author = "Dahui Zhou and Jeffrey Casavant and Graziani, \{Edmund I.\} and Haiyin He and Jeffrey Janso and Frank Loganzo and Sylvia Musto and Nathan Tumey and O'Donnell, \{Christopher J.\} and Russell Dushin",

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doi = "10.1016/j.bmcl.2019.01.009",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - Novel PIKK inhibitor antibody-drug conjugates

T2 - Synthesis and anti-tumor activity

AU - Zhou, Dahui

AU - Casavant, Jeffrey

AU - Graziani, Edmund I.

AU - He, Haiyin

AU - Janso, Jeffrey

AU - Loganzo, Frank

AU - Musto, Sylvia

AU - Tumey, Nathan

AU - O'Donnell, Christopher J.

AU - Dushin, Russell

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.

AB - Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.

KW - ADC

KW - Antitumor

KW - HER2-expressing tumor cell lines

KW - Neolymphostin

KW - PIKK inhibitor

KW - Trastuzumab conjugates

UR - https://www.scopus.com/pages/publications/85059838111

U2 - 10.1016/j.bmcl.2019.01.009

DO - 10.1016/j.bmcl.2019.01.009

M3 - Article

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SN - 0960-894X

VL - 29

SP - 943

EP - 947

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 7

ER -

Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity

Abstract

Keywords

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