Table 2.
Overview of Targeted Therapies in Acute Myeloid Leukemia, Which are Either Approved or Are Being Investigated in Clinical Trials
| Target | Therapeutic(s) | Mechanism of Action |
|---|---|---|
| PML-RARA | All-trans retinoic acid + arsenic trioxide | PML-RARA configuration change, which results in coregulator exchange; sumoylation and degradation of PML-RARA |
| Menin | Revumenib | Menin-MLL interaction inhibition |
| Ziftomenib | Menin-MLL interaction inhibition | |
| JNJ-6617 | Menin-MLL interaction inhibition | |
| DOT1L | Pinometostat | Specific DOT1L inhibition via conformational change |
| FLT3 | Type I (targeting FLT3-ITD and FLT3-TK) Midostaurin Crenolanib Gilterinib |
FLT3 inhibition, binds FLT3 receptor in active conformation |
| Type II (targeting FLT3-ITD) Quizartinib Sorafenib |
FLT3 inhibition, binds FLT3 receptor in inactive conformation | |
| Several kinases (KIT, SRC family, BCR-ABL, others) | Dasatinib | ATP-competitive protein tyrosine kinase inhibition |
| Mutated IDH1 | Ivosidenib | Selective allosteric inhibition of mutant IDH1 |
| Mutated IDH2 | Enasidenib | Selective allosteric inhibition of mutant IDH2 |
| Mutant p53 | Eprenetapopt | Covalent p53 core domain binding, partial restoration of WT function |
| XPO1 | Selinexor | Selective XPO1 inhibition |
| Eltanexor | Selective XPO1 inhibition | |
| SYK | Entospletinib | Selective SYK inhibition |
| RARα | Tamibarotene | RARα agonism |
| BCL2 | Venetoclax | BCL2 sequestration (BH3-mimetic) |
| MCL-1 | Murizatoclax | Selective MCL-1 inhibition |
| MEK | Cobimetinib | Selective MEK1 inhibition |
| MDM2 | Idasanutlin | p53-MDM2 interaction inhibition |
| Siremadlin | p53-MDM2 interaction inhibition | |
| Smoothened | Glasdegib | Inhibition of the translocation of Smoothened to the primary cilium |
| CD33 | Gemtuzumab ozogamicin | Gets internalized, subsequent calicheamicin causes DNA double-strand breaks |
| CD123 | Tagraxofusp | Anti-CD123 antibody fused to diphtheria toxin, gets internalized and blocks protein synthesis via eEF2 inhibition |
| Pivekimab sunirine | Anti-CD123 antibody fused to indolinobenzodiazepine pseudodimer payload, leading to DNA alkylation and single-strand breaks | |
| CD3/CD123 | Flotetuzumab, UCART123v1.2 | Anti-CD3/CD123 bispecific antibody; recruitment of T cells to CD123-expressing cells |
| CLL-1 | CAR-T cells | Recruitment of T cells to CLL-1-expressing cells |
| TIM-3 | Sabatolimab | Anti-TIM-3 monoclonal antibody—blockage of ligand binding |
| CD47/SIRPα | Magrolimab, TTI-621 | Inhibition of the CD47-SIRPα axis |
| AXL | Bemcentinib | Selective AXL inhibition |
| CTLA-4 | Ipilimumab | Anti-CTLA-4 monoclonal antibody—immune checkpoint inhibition |
| PD-1 | Nivolumab, pembrolizumab | Anti-PD-1 monoclonal antibody—immune checkpoint inhibition |
| GSPT1 | CC-90009 | Linkage of GSPT1 to an E3 ubiquitin ligase—promotes GSPT1 degradation |