Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)

Abstract

Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases.

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile

“…To overcome the problems of the aforementioned possible deboronation that might occur under strongly basic conditions associated with the typical synthesis of hydroxamic acids through hydroxylaminolysis, 40 we envisioned that a solid-phase synthesis as recently described by our group would be the suitable tool. 47 Beside the prevention of harsh basic conditions, this methodology could offer a fast Please do not adjust margins Please do not adjust margins and efficient carborane-based HDACi library expansion through a parallel synthesis approach. Consequently, we treated in a first step the commercially available 2-chlorotritylchloride resin 5 with N-hydroxyphthalimide to form the modified resin 6.…”

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

“…In another recent study, Sinatra et al described a series of temozolomide/HDACi and chlorambucil/HDACi hybrids [256]. The most promising hybrid, compound 3n, a chimeric compound based on the pharmacophores of chlorambucil and panobinostat, displayed improved anticancer properties compared to the sum of the activities of the respective control compounds alone, indicating a superadditive effect [256]. Chlordinaline, on the other hand, features the aminoanilide-based HDAC binding site of tacedinaline (CI-994) attached to the chlorambucil scaffold and displays moderate, but HDAC3-preferential inhibition and promising DNA damaging properties in vitro [255].…”

“…While dHDAC6 demonstrated efficient degradation of HDAC6 in MCF-7 breast cancer cells, the multiple myeloma cell line MM.1S was more sensitive to dHDAC6 in regard to degradation of HDAC6 [278,279]. Since the initial report by Yang et al, several other HDAC degraders have been disclosed, including selective HDAC6 PROTACs [256,[279][280][281][282][283], class I-selective PRO-TACs [284][285][286] and HDAC3-selective degraders [287]. Although most work has focused on hematological cancers so far, there are some encouraging results indicating that HDAC PROTACs could be an innovative new option for the treatment of solid cancers.…”

“…Chlordinaline, on the other hand, features the aminoanilide-based HDAC binding site of tacedinaline (CI-994) attached to the chlorambucil scaffold and displays moderate, but HDAC3-preferential inhibition and promising DNA damaging properties in vitro [ 255 ]. In another recent study, Sinatra et al described a series of temozolomide/HDACi and chlorambucil/HDACi hybrids [ 256 ]. The most promising hybrid, compound 3n, a chimeric compound based on the pharmacophores of chlorambucil and panobinostat, displayed improved anticancer properties compared to the sum of the activities of the respective control compounds alone, indicating a superadditive effect [ 256 ].…”

“…In another recent study, Sinatra et al described a series of temozolomide/HDACi and chlorambucil/HDACi hybrids [ 256 ]. The most promising hybrid, compound 3n, a chimeric compound based on the pharmacophores of chlorambucil and panobinostat, displayed improved anticancer properties compared to the sum of the activities of the respective control compounds alone, indicating a superadditive effect [ 256 ].…”