title: Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.
abstract: While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356μM and AR binding IC50=<0.03μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Jadhavar
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Sreekanth A
authors.initials: SA
authors.lastname: Ramachandran
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Riquelme
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Ashu
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.affiliation: Schrodinger, Inc., Portland, OR, USA.
authors.forename: Devleena
authors.initials: D
authors.lastname: Shivakumar
authors.affiliation: Schrodinger, Inc., Portland, OR, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ray
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Dnyaneshwar
authors.initials: D
authors.lastname: Zende
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Nayak
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Miglani
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Balaji D
authors.initials: BD
authors.lastname: Sathe
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Raja
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Olivia
authors.initials: O
authors.lastname: Farias
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Ivan
authors.initials: I
authors.lastname: Alfaro
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Belmar
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Guerrero
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Hung
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: jeffrey.lindquist@medivation.com.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Lindquist
authors.affiliation: Medivation, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: roopa.rai@hotmail.com.
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D000726:Androgen Antagonists; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Androgen receptor (AR) antagonist; Enzalutamide; HDAC6 inhibitor; Induced fit docking (IFD); Prostate cancer