Design, synthesis, and biological evaluation of bone-targeted proteasome inhibitors for multiple myeloma

Joseph K. Agyin; Bindu Santhamma; Sudipa S. Roy

doi:10.1016/j.bmcl.2013.09.043

Design, synthesis, and biological evaluation of bone-targeted proteasome inhibitors for multiple myeloma

Joseph K. Agyin, Bindu Santhamma, Sudipa S. Roy

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

12 Scopus citations

Abstract

Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. We have synthesized and evaluated the effects of the bone-targeted proteasome inhibitors PS-341-BP-1, PS-341-BP-2 and MG-262-BP on cell proliferation using the mouse 5TGM1 and human RPMI 8226 cell lines in vitro. The compounds exhibit strong cytotoxicity on MM cell lines and reduce the number of viable cells in a dose dependent manner.

Original language	English (US)
Pages (from-to)	6455-6458
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2013.09.043
State	Published - Dec 1 2013

Keywords

Bisphosphonate conjugate
Bone-targeted
Boronic acid
Multiple myeloma
Proteasome inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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title = "Design, synthesis, and biological evaluation of bone-targeted proteasome inhibitors for multiple myeloma",

abstract = "Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. We have synthesized and evaluated the effects of the bone-targeted proteasome inhibitors PS-341-BP-1, PS-341-BP-2 and MG-262-BP on cell proliferation using the mouse 5TGM1 and human RPMI 8226 cell lines in vitro. The compounds exhibit strong cytotoxicity on MM cell lines and reduce the number of viable cells in a dose dependent manner.",

keywords = "Bisphosphonate conjugate, Bone-targeted, Boronic acid, Multiple myeloma, Proteasome inhibitor",

author = "Agyin, {Joseph K.} and Bindu Santhamma and Roy, {Sudipa S.}",

note = "Funding Information: This work was supported by Grants KO1 CA113468 and P30 CA054174 (to J.K.A.) from the National Cancer Institute , and by Grants from the Kerr, and William & Ella Owens Research Foundations (J.K.A.). ",

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doi = "10.1016/j.bmcl.2013.09.043",

language = "English (US)",

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AU - Agyin, Joseph K.

AU - Santhamma, Bindu

AU - Roy, Sudipa S.

N1 - Funding Information: This work was supported by Grants KO1 CA113468 and P30 CA054174 (to J.K.A.) from the National Cancer Institute , and by Grants from the Kerr, and William & Ella Owens Research Foundations (J.K.A.).

PY - 2013/12/1

Y1 - 2013/12/1

N2 - Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. We have synthesized and evaluated the effects of the bone-targeted proteasome inhibitors PS-341-BP-1, PS-341-BP-2 and MG-262-BP on cell proliferation using the mouse 5TGM1 and human RPMI 8226 cell lines in vitro. The compounds exhibit strong cytotoxicity on MM cell lines and reduce the number of viable cells in a dose dependent manner.

AB - Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. We have synthesized and evaluated the effects of the bone-targeted proteasome inhibitors PS-341-BP-1, PS-341-BP-2 and MG-262-BP on cell proliferation using the mouse 5TGM1 and human RPMI 8226 cell lines in vitro. The compounds exhibit strong cytotoxicity on MM cell lines and reduce the number of viable cells in a dose dependent manner.

KW - Bisphosphonate conjugate

KW - Bone-targeted

KW - Boronic acid

KW - Multiple myeloma

KW - Proteasome inhibitor

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ER -

Design, synthesis, and biological evaluation of bone-targeted proteasome inhibitors for multiple myeloma

Abstract

Keywords

ASJC Scopus subject areas

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