Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia.

Journal of Medicinal Chemistry
Krimo ToutahPatrick T Gunning

Abstract

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.

References

Oct 6, 2001·Cancer Chemotherapy and Pharmacology·P P Pandolfi
May 25, 2002·Nature·Charlotte HubbertTso-Pang Yao
Feb 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Emma HocklyGillian P Bates
Feb 28, 2003·The EMBO Journal·Yu ZhangPatrick Matthias
Apr 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Stephen J HaggartyStuart L Schreiber
May 2, 2003·Annals of the New York Academy of Sciences·Sam ThiagalingamJose F Ponte
May 1, 1964·Proceedings of the National Academy of Sciences of the United States of America·V G ALLFREYA E MIRSKY
Jan 21, 2004·Nature Reviews. Cancer·Andrew P Feinberg, Benjamin Tycko
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Apr 8, 2004·Neoplasia : an International Journal for Oncology Research·Daniel R RhodesArul M Chinnaiyan
Oct 7, 2004·Genes & Development·Anders H Lund, Maarten van Lohuizen
Mar 29, 2007·Journal of Cell Science·Andy Dong-Anh TranJ Chloë Bulinski
Apr 10, 2007·International Journal of Cancer. Journal International Du Cancer·Takashi KumagaiH Phillip Koeffler
Jan 9, 2008·Molecular and Cellular Biology·Yu ZhangPatrick Matthias
Jul 17, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Leigh EllisH Miles Prince
Jul 22, 2010·Expert Review of Anticancer Therapy·Cliona GrantSusan E Bates
Aug 30, 2011·Current Opinion in Structural Biology·Patrick M LombardiDavid W Christianson
Jun 1, 2012·Blood·Claire Dearden
Sep 27, 2012·Journal of Medicinal Chemistry·Joel A BergmanAlan P Kozikowski
Feb 19, 2013·Clinical Science·Jinhua TangShougang Zhuang
Sep 23, 2014·Trends in Pharmacological Sciences·Oliver H KrämerAndreas Sellmer
Mar 25, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Hyon-Zu LeeRichard Pazdur
Aug 2, 2015·Journal of Biomolecular Screening·Geetha PadigeMary Kay H Pflum
Sep 8, 2015·Epigenomics·Wenji YanMingzhou Guo
Dec 8, 2015·The New England Journal of Medicine·Andrew W RobertsJohn F Seymour
Nov 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Teru HideshimaJames E Bradner
Jan 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dan T VoglSagar Lonial
Mar 21, 2017·Apoptosis : an International Journal on Programmed Cell Death·Maria CosenzaSamantha Pozzi
Jul 4, 2017·International Journal of Molecular Sciences·Tomas EckschlagerJan Hrabeta

❮ Previous
Next ❯

Software Mentioned

Epik
Excel
XLfit
LigPrep
ImageJ
Oncomine
Maestro
Image lab
Prime
Schrödinger Maestro

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.