Discovery and Development of Farydak (NVP‐LBH589, Panobinostat) as an Anticancer Drug

Abstract

Target Identification: From p21 Waf1 Induction to HDAC InhibitionFor cancer cell biology the discoveries in the seventies and eighties on how normal cells grow and divide were the basis for understanding the initiation and progression of cancer [1]. From various biochemical and genetic studies the different phases of the cell cycle were characterised and the regulatory pathways controlling the cycle cell were identified [2,3]. By the early nineties additional studies had shown that in mammalian cells the passage from G1 to S phase in the cell cycle (Figure 4.1) was controlled by the enzymatic activity of cyclin-dependent kinase 2 (CDK2) and that the inhibition of CDK2 activity resulted in cell cycle arrest at G1 [4][5][6][7]. A key regulator of CDK2 activity was found to be the protein p21 Waf1 , which by its complexation with CDK2 effectively blocks the phosphorylation of Rb by decreasing the levels of the cyclin(A,E)-CDK2 complexes [8][9][10].These advances in the understanding of how gene expression regulates cell cycle progression inspired our search for anticancer agents targeting cell cycle regulators. The discovery of the CDK2 inhibitor, p21 Waf1 , as a downstream transcription p21 S G2

Chondroprotective Effects of a Histone Deacetylase Inhibitor, Panobinostat, on Pain Behavior and Cartilage Degradation in Anterior Cruciate Ligament Transection-Induced Experimental Osteoarthritic Rats

“…in 1987 [ 5 ]. At first, PSA was discovered as an HDAC inhibitor for anticancer properties from p21, a cyclin-dependent kinase 2 promoter assay system [ 6 , 7 ]. Due to the weak physiological stability of PSA, medicinal chemists attempted to improve its chemical properties [ 8 ].…”

“…Due to the weak physiological stability of PSA, medicinal chemists attempted to improve its chemical properties [ 8 ]. Although several interesting derivatives were developed, the pharmacological profile of PSA was not improved successfully [ 7 , 8 ]. Subsequently, another natural compound, trichostatin A (also an HDAC inhibitor), was isolated using the same p21 promoter assay [ 7 , 8 , 9 ].…”

“…Although several interesting derivatives were developed, the pharmacological profile of PSA was not improved successfully [ 7 , 8 ]. Subsequently, another natural compound, trichostatin A (also an HDAC inhibitor), was isolated using the same p21 promoter assay [ 7 , 8 , 9 ]. LAK974 was synthesized based on the analysis of a two-dimensional pharmacophore model of trichostatin A; however, LAK974 showed significant activity in vitro but poor efficacy in vivo [ 7 ].…”

“…Subsequently, another natural compound, trichostatin A (also an HDAC inhibitor), was isolated using the same p21 promoter assay [ 7 , 8 , 9 ]. LAK974 was synthesized based on the analysis of a two-dimensional pharmacophore model of trichostatin A; however, LAK974 showed significant activity in vitro but poor efficacy in vivo [ 7 ]. Structure modification was continued by computational docking studies to obtain LAQ824, which showed increased antiproliferative effects in several cancer cell lines (including A549 (lung), HCT166 (colon), and MDA435 (breast)) and decreased apoptotic death in normal human dermal fibroblasts [ 7 ].…”

“…LAK974 was synthesized based on the analysis of a two-dimensional pharmacophore model of trichostatin A; however, LAK974 showed significant activity in vitro but poor efficacy in vivo [ 7 ]. Structure modification was continued by computational docking studies to obtain LAQ824, which showed increased antiproliferative effects in several cancer cell lines (including A549 (lung), HCT166 (colon), and MDA435 (breast)) and decreased apoptotic death in normal human dermal fibroblasts [ 7 ]. As the safety of LAQ824 in preclinical development was unclear and induced a body weight loss problem in vivo [ 7 ], LBH589 was finally optimized by further synthetic design and showed a significant tumor regression effect in an HCT116 xenograft model with minimal body weight loss [ 7 , 8 ].…”