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.
The multicomponent synthesis of a mini library of histone deacetylase inhibitors with imidazo[1,2-a]pyridine-based cap groups is presented. The biological evaluation led to the discovery of the hit compound MAIP-032 as a selective HDAC6 inhibitor with promising anticancer activity. The X-ray structure of catalytic domain 2 from Danio rerio HDAC6 complexed with MAIP-032 revealed a monodentate zinc-binding mode.
In this work, we utilized the proteolysis targeting chimera
(PROTAC)
technology to achieve the chemical knock-down of histone deacetylase
6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized
via a solid-phase parallel synthesis approach, which allowed the rapid
preparation of two HDAC6 degrader mini libraries. The PROTACs were
either based on an unselective vorinostat-like HDAC ligand or derived
from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated
selective degradation of HDAC6 in leukemia cell lines. The best degraders
from each series (denoted A6 and B4) were
capable of degrading HDAC6 via ternary complex formation and the ubiquitin–proteasome
pathway, with DC50 values of 3.5 and 19.4 nM, respectively.
PROTAC A6 demonstrated promising antiproliferative activity
via inducing apoptosis in myeloid leukemia cell lines. These findings
highlight the potential of this series of degraders as effective pharmacological
tools for the targeted degradation of HDAC6.
Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC: 4 nM; Pf Dd2 IC: 1 nM) and P. berghei exo-erythrocytic forms (Pb EEF IC: 25 nM) with promising parasite-specific activity (SI: 2496, SI: 9990, and SI: 400).
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