Promising targeted agents in T-ALL and their stage in clinical testing
| Compound . | Specificity . | Clinical phase . | Disease . |
|---|---|---|---|
| NOTCH1 signaling | |||
| MK-0752 | GSI | Phase 1 | T-ALL and lymphoma |
| PF-03084014 | GSI | Phase 1 | Advanced-stage cancers, T-ALL, lymphoblastic lymphoma |
| BMS-906024 (with dexamethasone) | GSI | Phase 1 | T-ALL or T-cell lymphoblastic lymphoma |
| OMP-52M51 | Notch1 inhibitory antibody | Phase 1 | Dose-escalation study in lymphoid malignancy |
| LY3039478 | Notch1 inhibitor | Phase 1 | Dose-escalation study in advanced-stage cancers |
| BMS-536924 | ATP-competitive IGF-1R/IR inhibitor | Preclinical | |
| JAK-STAT inhibitors | |||
| Ruxolitinib | JAK1/2 inhibitor | Phase 1 | AML |
| Phase 2 | B-ALL | ||
| FDA approved | Myelofibrosis | ||
| Phase 1/2 | Fallopian tube cancer, ovarian cancer, primary peritoneal cancer | ||
| Tofacitinib | JAK3 inhibitor | FDA approved | Rheumatoid arthritis |
| Phase 1 | Systemic lupus erythematosus | ||
| Phase 3 | Juvenile idiopathic arthritis | ||
| Pimozide | STAT5 inhibitor | FDA approved | Schizophrenia, psychotic disorders |
| Phase 2 | Amyotrophic lateral sclerosis | ||
| 17-AAG | HSP90 inhibitor | Phase 3 | Multiple myeloma |
| Phase 2 | Pancreatic cancer | ||
| Phase 2 | Advanced malignancies | ||
| Phase 2 | Ovarian cancer | ||
| PU-H71 | HSP90 inhibitor | Phase 1 | Solid tumor, lymphoma |
| Phase 1 | Metastatic solid tumor, lymphoma, myeloproliferative neoplasms | ||
| Inducers of apoptosis | |||
| ABT-263 (Navitoclax) | Inhibitor of Bcl-xL, Bcl-2, and Bcl-w | Phase 1 | Non-small cell lung cancer |
| Phase 2 | Platinum-resistant or refractory ovarian cancer | ||
| Phase 1 | Hepatocellular carcinoma | ||
| Phase 1/2 | Melanoma | ||
| ABT-199 (Venetoclax) | Bcl-2–selective inhibitor | FDA approved | CLL |
| Phase 3 | Relapsed/refractory multiple myeloma | ||
| PI3K inhibitors | |||
| CAL-130 | Inhibits p110γ and p110δ catalytic domains | Preclinical | |
| Ly294002 | Inhibit PI3Kα/δ/β | Phase 1 | Neuroblastoma |
| Pictilisib (GDC-0941) | Inhibitor of PI3Kα/δ | Phase 2 | Breast cancer |
| Phase 2 | Nonsquamous non-small cell lung cancer | ||
| Apitolisib (GDC-0980, RG7422) | Inhibitor for PI3Kα/β/δ/γ | Phase 2 | Endometrial carcinoma |
| Phase 1/2 | Prostate cancer | ||
| Phase 2 | Renal cell carcinoma | ||
| MEK inhibitors | |||
| CI-1040 | ATP noncompetitive MEK1/2 inhibitor | Phase 2 | Breast cancer, colorectal cancer, lung cancer, pancreatic cancer |
| Selumetinib (AZD6244) | MEK1 inhibitor | Phase 2 | Triple-negative breast cancer |
| Phase 1 | Lung cancer, melanoma, head and neck carcinoma, gastroesophageal cancer, breast cancer, pancreatic adenocarcinoma, colorectal cancer | ||
| Trametinib (GSK1120212) | MEK1/2 inhibitor | Phase 2 | Gastrointestinal stromal tumors |
| Phase 1 | Melanoma | ||
| Phase 1 | Neuroblastoma | ||
| Phase 2 | Non-small cell lung cancer | ||
| ABL inhibitors | |||
| Imatinib | v-Abl, c-Kit, and PDGFR inhibitor | FDA approved | Chronic myeloid leukemia |
| Phase 2 | B-ALL, B lymphoblastic lymphoma, T-ALL, T lymphoblastic lymphoma | ||
| Phase 3 | Philadelphia chromosome–positive adult ALL | ||
| Dasatinib | Abl, Src, and c-Kit inhibitor | FDA approved | Chronic myeloid leukemia |
| Phase 2 | ALL | ||
| Phase 1 | Chronic kidney disease | ||
| Nilotinib | Abl, Src, and c-Kit inhibitor | Phase 2 | Glioma |
| Phase 3 | Philadelphia chromosome–positive adult ALL | ||
| FDA approved | Chronic myeloid leukemia | ||
| Hedgehog inhibitors | |||
| Vismodegib (GDC-0449) | SMO inhibitor | FDA approved | Basal cell carcinoma |
| Phase 2 | Breast cancer | ||
| Phase 2 | Non-Hodgkin lymphoma, multiple myeloma, advanced solid tumors | ||
| GANT61 | GLI1 inhibitor | Preclinical | |
| Translation inhibitors | |||
| Rapamycin | Specific mTOR inhibitor | Phase 2 | Myelodysplastic syndrome, CLL, ALL, T lymphoblastic lymphoma, acute myelogenous leukemia, acute biphenotypic leukemia, acute undifferentiated leukemia |
| Phase 1 | Fallopian tube carcinoma, ovarian carcinoma, primary peritoneal carcinoma | ||
| 4EGI-1 | Competitive eIF4E/eIF4G interaction inhibitor | Preclinical |
| Compound . | Specificity . | Clinical phase . | Disease . |
|---|---|---|---|
| NOTCH1 signaling | |||
| MK-0752 | GSI | Phase 1 | T-ALL and lymphoma |
| PF-03084014 | GSI | Phase 1 | Advanced-stage cancers, T-ALL, lymphoblastic lymphoma |
| BMS-906024 (with dexamethasone) | GSI | Phase 1 | T-ALL or T-cell lymphoblastic lymphoma |
| OMP-52M51 | Notch1 inhibitory antibody | Phase 1 | Dose-escalation study in lymphoid malignancy |
| LY3039478 | Notch1 inhibitor | Phase 1 | Dose-escalation study in advanced-stage cancers |
| BMS-536924 | ATP-competitive IGF-1R/IR inhibitor | Preclinical | |
| JAK-STAT inhibitors | |||
| Ruxolitinib | JAK1/2 inhibitor | Phase 1 | AML |
| Phase 2 | B-ALL | ||
| FDA approved | Myelofibrosis | ||
| Phase 1/2 | Fallopian tube cancer, ovarian cancer, primary peritoneal cancer | ||
| Tofacitinib | JAK3 inhibitor | FDA approved | Rheumatoid arthritis |
| Phase 1 | Systemic lupus erythematosus | ||
| Phase 3 | Juvenile idiopathic arthritis | ||
| Pimozide | STAT5 inhibitor | FDA approved | Schizophrenia, psychotic disorders |
| Phase 2 | Amyotrophic lateral sclerosis | ||
| 17-AAG | HSP90 inhibitor | Phase 3 | Multiple myeloma |
| Phase 2 | Pancreatic cancer | ||
| Phase 2 | Advanced malignancies | ||
| Phase 2 | Ovarian cancer | ||
| PU-H71 | HSP90 inhibitor | Phase 1 | Solid tumor, lymphoma |
| Phase 1 | Metastatic solid tumor, lymphoma, myeloproliferative neoplasms | ||
| Inducers of apoptosis | |||
| ABT-263 (Navitoclax) | Inhibitor of Bcl-xL, Bcl-2, and Bcl-w | Phase 1 | Non-small cell lung cancer |
| Phase 2 | Platinum-resistant or refractory ovarian cancer | ||
| Phase 1 | Hepatocellular carcinoma | ||
| Phase 1/2 | Melanoma | ||
| ABT-199 (Venetoclax) | Bcl-2–selective inhibitor | FDA approved | CLL |
| Phase 3 | Relapsed/refractory multiple myeloma | ||
| PI3K inhibitors | |||
| CAL-130 | Inhibits p110γ and p110δ catalytic domains | Preclinical | |
| Ly294002 | Inhibit PI3Kα/δ/β | Phase 1 | Neuroblastoma |
| Pictilisib (GDC-0941) | Inhibitor of PI3Kα/δ | Phase 2 | Breast cancer |
| Phase 2 | Nonsquamous non-small cell lung cancer | ||
| Apitolisib (GDC-0980, RG7422) | Inhibitor for PI3Kα/β/δ/γ | Phase 2 | Endometrial carcinoma |
| Phase 1/2 | Prostate cancer | ||
| Phase 2 | Renal cell carcinoma | ||
| MEK inhibitors | |||
| CI-1040 | ATP noncompetitive MEK1/2 inhibitor | Phase 2 | Breast cancer, colorectal cancer, lung cancer, pancreatic cancer |
| Selumetinib (AZD6244) | MEK1 inhibitor | Phase 2 | Triple-negative breast cancer |
| Phase 1 | Lung cancer, melanoma, head and neck carcinoma, gastroesophageal cancer, breast cancer, pancreatic adenocarcinoma, colorectal cancer | ||
| Trametinib (GSK1120212) | MEK1/2 inhibitor | Phase 2 | Gastrointestinal stromal tumors |
| Phase 1 | Melanoma | ||
| Phase 1 | Neuroblastoma | ||
| Phase 2 | Non-small cell lung cancer | ||
| ABL inhibitors | |||
| Imatinib | v-Abl, c-Kit, and PDGFR inhibitor | FDA approved | Chronic myeloid leukemia |
| Phase 2 | B-ALL, B lymphoblastic lymphoma, T-ALL, T lymphoblastic lymphoma | ||
| Phase 3 | Philadelphia chromosome–positive adult ALL | ||
| Dasatinib | Abl, Src, and c-Kit inhibitor | FDA approved | Chronic myeloid leukemia |
| Phase 2 | ALL | ||
| Phase 1 | Chronic kidney disease | ||
| Nilotinib | Abl, Src, and c-Kit inhibitor | Phase 2 | Glioma |
| Phase 3 | Philadelphia chromosome–positive adult ALL | ||
| FDA approved | Chronic myeloid leukemia | ||
| Hedgehog inhibitors | |||
| Vismodegib (GDC-0449) | SMO inhibitor | FDA approved | Basal cell carcinoma |
| Phase 2 | Breast cancer | ||
| Phase 2 | Non-Hodgkin lymphoma, multiple myeloma, advanced solid tumors | ||
| GANT61 | GLI1 inhibitor | Preclinical | |
| Translation inhibitors | |||
| Rapamycin | Specific mTOR inhibitor | Phase 2 | Myelodysplastic syndrome, CLL, ALL, T lymphoblastic lymphoma, acute myelogenous leukemia, acute biphenotypic leukemia, acute undifferentiated leukemia |
| Phase 1 | Fallopian tube carcinoma, ovarian carcinoma, primary peritoneal carcinoma | ||
| 4EGI-1 | Competitive eIF4E/eIF4G interaction inhibitor | Preclinical |
ATP, adenosine triphosphate; FDA, US Food and Drug Administration; HSP90, heat shock protein 90; PDGFR, platelet-derived growth factor receptor; SMO, smoothened.