Table 2. . Molecules targeted for the development of new anti-acute myeloid leukemia therapy, their abnormalities in leukemic cells, their pharmacologic targeting and ongoing clinical trials.
| Biochemical target | AML-related alteration | Mode of action | Target ‘drugable’ | Drugs |
|---|---|---|---|---|
| NPM1 | Mutated in 30–40% of AMLs | Nucleolar component | Compounds inducing NPM1 degradation: – ATRA – ATO Compound inhibiting NPM1-mediated gene expression: – Menin-MLL1 – inhibitors – DTO1L inhibitors |
ATRA and ATO MI-503 (inhibitor of menin-MLL1) and EPZ4777 (DTO1L inhibitor) |
| IDH1 and IDH2 | Mutated in about 10% AMLs | Conversion of isocitrate to α-keto-glutarate Mutant enzymes acquire a neomorphic function: isocitrate is converted to R2-hydroxyglutarate |
Small-molecule inhibitors (AG-120: inhibitor of IDH1 enzyme AG-221: inhibitor of IDH2 enzyme) |
AG-120 (NCT 02074839) AG-221 (NCT 01915498, NCT 02577406) |
| FLT3 | FLT3–ITD: about 25% AMLs FLT3-TKD: about 10% AMLs |
Receptor tyrosine kinase for FLT3 ligand Mutant receptors display constitutive receptor activation |
Small-molecule multikinase inhibitors with activity against mutant FLT3 in AMLs: sorafenib, midostaurin, quizartinib, crenolanib | Sorafenib (NCT02196857, NCT01253070) Midostaurin (NCT00651261) Quizartinib (NCT01892371, NCT02039726) Crenolanib (NCT016557682, NCT02400281, NCT02283177) |
| CD33 | Increased CD33 expression on leukemic blasts compared with normal bone marrow myeloid precursors | Member of the SIGLECS Myeloid differentiation antigen not expressed on HSCs |
Specific mAbs. SGN-33A: mAb drug conjugated directed at CD33 AMG-330: monoclonal bispecific antibody directed at CD33 and CD3. |
SGN-33A (NCT02326584, NCT019002329) AMG-330 (NCT02520427) |
| CD123 (IL-3R alpha chain) | CD123 is overexpressed on AML leukemic blasts, compared with BM myeloid precursors. CD123 is expressed on leukemic stem cells, but not on normal HSCs |
High-affinity receptor for IL-3. The activated IL-3 plays multiple biological functions, being involved in the control of normal and malignant hemopoiesis, native and adaptive immunity and inflammatory response | Specific mAbs or IL-3 ligand SL401: recombinant human IL-3 fused to truncated diphtheria toxin Talacotuzumab (CSL362): mAb to human IL-3R alpha chain IMGN362: anti-CD123 drug-conjugate |
SL 401 (NCT02113982) Talacotuzumab (NCT02472145, NCT01632852) |
AML: Acute myeloid leukemia; ATO: Arsenic trioxide; ATRA: All-trans retinoic acid; BM: Bone marrow; FLT3: Fms-like tyrosine kinase; HSC: Hematopoietic stem cell; ITD: Internal tandem duplication; mAb: Monoclonal antibody; SIGLECS: Sialic acid-binding immunoglobulin-like lectins; TKD: Tyrosine kinase domain.