Expanding the antileukemic potential of HDAC inhibitors in combination therapy with Ubiquitin-Proteasome System (UPS) modulators

• Applicants: Dr. Sanil Bhatia; Professor Dr. Thomas Kurz
• Subject Area: Pharmacy
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528968169

The first-line therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and anthracycline. Despite the effectiveness of this combination, problems regarding patient tolerance and resistance to this therapy have been observed. Due to these limitations, new therapeutic regimens are currently being developed. Histone deacetylase inhibitors (HDACi) have recently emerged as a promising epigenetic therapeutic option, especially in the treatment of hematological cancers, and have displayed a favorable response in early clinical trials recruiting relapsed/refractory AML patients. However, despite their clinical potential, pure pan-HDACi (like panobinostat) are typically linked with severe side effects. Because of insufficient anti-cancer efficacy as mono treatment and resistant development, HDACi cannot be used without a combination partner. Therefore, we have focused on developing more class-specific HDACi, such as class I, IIb HDACi, HDAC-PROTACs and finding novel synergistic combinations for relapsed/refractory leukemia. Structural optimizations afforded the improved alkoxyamide-based HDAC class I, IIb inhibitor LAK41 (8a) with more robust antileukemia activity than the clinical candidate ricolinostat. The most promising combinations were found between HDAC inhibitors and Ubiquitin-Proteasome System (UPS) modulators. Moreover, a comparatively stronger synergism between the combination of HDAC inhibitor LAK41 (8a) and the proteasome inhibitors bortezomib and carfilzomib was noticed against AML leukemia cells than acute lymphoblastic leukemia cells (ALL). Thus, to further optimize our lead candidate LAK41 (8a), here we propose (i) synthesis of improved analogs of LAK41 (8a); (ii) development of dual-targeting non-peptide HDAC-proteasome inhibitors; (iii) development of HDAC-PROTACs targeting HDAC class I and IIb; (iv) their selection; (v) biological in vitro; (vi) and in vivo evaluation for their antileukemic activity, especially against AML cells.

• DFG Programme: Research Grants