An overview of early efforts in targeting BCL-2 family protein inhibitors
| Name . | Compound/Targets . | Preclinical data . | Indication . | Combination therapy . | Comments . | Clinical phase . | Trial . | Reference . |
|---|---|---|---|---|---|---|---|---|
| Pan inhibitors | ||||||||
| Gossypol compounds (AT-101) | Natural polyphenolic aldehyde derivatives | Efficacy in CLL cells in vitro. AT-101 overcame microenvironment-mediated resistance93,137 | R/R CLL | AT-101 plus rituximab | Modest ORR of 42% with no CRs | 2 | 138 | |
| BCL-2/BCL-xL | ||||||||
| Lactate dehydrogenase | ||||||||
| Obatoclax (GX15-070) | Small molecule inhibitor | Promising results in vitro | Monotherapy | |||||
| BCL-2, BCL-xL, BCL-w MCL-1 | May cause cells to die via autophagy and necroptosis rather than apoptosis139 | R/R HL | — | No objective response | 1 | NCT00359892 | 140 | |
| TN MDS | — | ORR 8% | 2 | NCT00413114 | 141 | |||
| R/R CLL | — | PR 4%, neurologic toxicities was a dose limiting factor | 1 | NCT00600964 | 142 | |||
| Combination therapy | ||||||||
| TN FL | Obatoclax alone or in combination with R | No activity of single-agent obatoclax. | 2 | NCT00427856 | 143 | |||
| R/R CLL | Obatoclax plus FR vs FR alone | ORR 54% (all PRs) equivalent to FR alone | 2 | NCT00612612 | 144 | |||
| R/R MCL | Obatoclax plus bortezomib vs bortezomib alone | ORR 31%, equivalent to historical observations on bortezomib alone | 1/2 | NCT00407303 | 145 | |||
| Navitoclax (ABT263) | Small molecule inhibitor | Remarkable efficacy in preclinical studies, high affinity (>1000× that seen with earlier molecules)52,55 | Monotherapy | |||||
| BCL-2, BCL-xL, BCL-w | R/R CLL | — | PR of 35%. Reduction of lymphocytosis >50% observed in 19/21 patients. Grade 3/4 thrombocytopenia observed in 28% of patients | 1 | NCT00481091 | 58 | ||
| Combination therapy | ||||||||
| ALL cells are both BCL-2 and BCL-xL dependent102 | R/R ALL/LL | Navitoclax, VEN, Peg-asparaginase, Vincristine, TKIs, Dexamethasone. | Recruiting | 1 | NCT03181126 | |||
| Targeting both JAK2 and BCL2/BCLxL overcome resistance to JAK2 inhibitors in JAK2 driven malignancies146 | Myelofibrosis | Navitoclax plus ruxolitinib (JAK inhibitor) | Recruiting | 2 | NCT03222609 | |||
| BCL-2 inhibitors | ||||||||
| PNT2258 | Liposomal encapsulated DNA interference oligonucleotide nanoparticle | Antitumor activity in NHL xenografts | R/R NHL | 11/13 achieved clinical benefit from treatment | 2 | NCT01733238 | 147 | |
| BCL-2 gene | R/R DLBCL | ORR of 8.1% with single-agent therapy | 2 | NCT02226965 | 148 | |||
| Further development of the drug was suspended | ||||||||
| Oblimersen sodium/ G3139/augmerosen | Antisense oligonucleotide | Induced apoptosis in B-cell lymphoma cell lines149-151 | NHL | Oblimersen plus R | Modest efficacy (PR in 8% of CLL patients). No pharmaco-dynamic marker of reducing BCL-2 was reported | 1/2 | 152 | |
| BCL-2 | R/R CLL | Oblimersen, cyclophosphamide, and fludarabine | No significant difference in OS between the 2 groups | 3 | 153 | |||
| Further development of the drug was halted |
| Name . | Compound/Targets . | Preclinical data . | Indication . | Combination therapy . | Comments . | Clinical phase . | Trial . | Reference . |
|---|---|---|---|---|---|---|---|---|
| Pan inhibitors | ||||||||
| Gossypol compounds (AT-101) | Natural polyphenolic aldehyde derivatives | Efficacy in CLL cells in vitro. AT-101 overcame microenvironment-mediated resistance93,137 | R/R CLL | AT-101 plus rituximab | Modest ORR of 42% with no CRs | 2 | 138 | |
| BCL-2/BCL-xL | ||||||||
| Lactate dehydrogenase | ||||||||
| Obatoclax (GX15-070) | Small molecule inhibitor | Promising results in vitro | Monotherapy | |||||
| BCL-2, BCL-xL, BCL-w MCL-1 | May cause cells to die via autophagy and necroptosis rather than apoptosis139 | R/R HL | — | No objective response | 1 | NCT00359892 | 140 | |
| TN MDS | — | ORR 8% | 2 | NCT00413114 | 141 | |||
| R/R CLL | — | PR 4%, neurologic toxicities was a dose limiting factor | 1 | NCT00600964 | 142 | |||
| Combination therapy | ||||||||
| TN FL | Obatoclax alone or in combination with R | No activity of single-agent obatoclax. | 2 | NCT00427856 | 143 | |||
| R/R CLL | Obatoclax plus FR vs FR alone | ORR 54% (all PRs) equivalent to FR alone | 2 | NCT00612612 | 144 | |||
| R/R MCL | Obatoclax plus bortezomib vs bortezomib alone | ORR 31%, equivalent to historical observations on bortezomib alone | 1/2 | NCT00407303 | 145 | |||
| Navitoclax (ABT263) | Small molecule inhibitor | Remarkable efficacy in preclinical studies, high affinity (>1000× that seen with earlier molecules)52,55 | Monotherapy | |||||
| BCL-2, BCL-xL, BCL-w | R/R CLL | — | PR of 35%. Reduction of lymphocytosis >50% observed in 19/21 patients. Grade 3/4 thrombocytopenia observed in 28% of patients | 1 | NCT00481091 | 58 | ||
| Combination therapy | ||||||||
| ALL cells are both BCL-2 and BCL-xL dependent102 | R/R ALL/LL | Navitoclax, VEN, Peg-asparaginase, Vincristine, TKIs, Dexamethasone. | Recruiting | 1 | NCT03181126 | |||
| Targeting both JAK2 and BCL2/BCLxL overcome resistance to JAK2 inhibitors in JAK2 driven malignancies146 | Myelofibrosis | Navitoclax plus ruxolitinib (JAK inhibitor) | Recruiting | 2 | NCT03222609 | |||
| BCL-2 inhibitors | ||||||||
| PNT2258 | Liposomal encapsulated DNA interference oligonucleotide nanoparticle | Antitumor activity in NHL xenografts | R/R NHL | 11/13 achieved clinical benefit from treatment | 2 | NCT01733238 | 147 | |
| BCL-2 gene | R/R DLBCL | ORR of 8.1% with single-agent therapy | 2 | NCT02226965 | 148 | |||
| Further development of the drug was suspended | ||||||||
| Oblimersen sodium/ G3139/augmerosen | Antisense oligonucleotide | Induced apoptosis in B-cell lymphoma cell lines149-151 | NHL | Oblimersen plus R | Modest efficacy (PR in 8% of CLL patients). No pharmaco-dynamic marker of reducing BCL-2 was reported | 1/2 | 152 | |
| BCL-2 | R/R CLL | Oblimersen, cyclophosphamide, and fludarabine | No significant difference in OS between the 2 groups | 3 | 153 | |||
| Further development of the drug was halted |
ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; FR, fludarbine + rituximab; HL, Hodgkin lymphoma; LL, lymphoblastic lymphoma; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; ORR, overall response rate; OS, overall survival; PR, partial response; R/R, relapsed/refractory; R, rituximab; TKI, tyrosine kinase inhibitor; TLS, tumor lysis syndrome; TN, treatment naive; VEN, venetoclax.