- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Journal, IO biomarker: The multi-kinase inhibitor CG-806 exerts anti-cancer activity against acute myeloid leukemia by co-targeting FLT3, BTK, and aurora kinases. (Pubmed Central) - Nov 13, 2024
P1
The results of this study suggest that CG-806 is a promising multi-kinase inhibitor with anti-leukemic efficacy regardless of FLT3 mutational status. A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).Key pointsThe multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status.CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases.Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells.
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - Sep 2, 2024
P1, N=160, Active, not recruiting,
A phase 1 clinical trial of CG-806 for the treatment of AML has been initiated (NCT04477291).Key pointsThe multi-kinase inhibitor CG-806 exerts superior anti-leukemic activity in AML, regardless of its FLT3 status.CG-806 triggered G1 arrest in FLT3 mutated cells and G2/M arrest in FLT3 WT cells through the suppression of FLT3/BTK and aurora kinases.Concomitantly targeting FLT3 and Bcl-2 and/or Mcl-1 exerted synergistic pro-apoptotic effects on both FLT3 WT and mutated AML cells. Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - Sep 2, 2024
P1, N=80, Active, not recruiting,
Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024 Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - Dec 15, 2023
P1, N=160, Active, not recruiting,
Trial completion date: Dec 2024 --> May 2025 | Trial primary completion date: Feb 2024 --> Dec 2024 Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Feb 2024
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Enrollment closed, Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - Dec 15, 2023
P1, N=80, Active, not recruiting,
Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Feb 2024 Recruiting --> Active, not recruiting | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Feb 2024
- |||||||||| CLL Targets Beyond BTKi and Bcl2i (HALL A) - May 20, 2023 - Abstract #ICLLM2023ICLLM_55;
Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-? inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Journal: Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma. (Pubmed Central) - Mar 13, 2023
These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells.
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - Jan 5, 2023
P1, N=80, Recruiting,
The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells. Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Nov 2022 --> Nov 2023
- |||||||||| Extended Abstract: New BTKi () - Sep 22, 2022 - Abstract #SOHO2022SOHO_372;
Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Journal: Luxeptinib (CG-806) targets FLT3 and clusters of kinases operative in acute myeloid leukemia. (Pubmed Central) - Jul 9, 2022
Luxeptinib administered continuously PO every 12 h at a dose that yielded a mean Cmin plasma concentration of 1.0 {plus minus} 0.3 µM (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase 1 trial for patients with AML and myelodysplastic/myeloproliferative neoplasms (MDS/MPN).
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Trial completion date, Trial primary completion date: A Study of CG-806 in Patients With Relapsed or Refractory CLL/SLL or Non-Hodgkin's Lymphomas (clinicaltrials.gov) - Feb 24, 2022
P1, N=160, Recruiting,
The Bcl-2 network is a key mediator of sensitivity to CG-806 and combined targeting of Bcl-2 demonstrates synergy with CG-806 warranting continued exploration in lymphoid malignancies. Trial completion date: May 2022 --> May 2023 | Trial primary completion date: Dec 2021 --> Sep 2022
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Journal: Luxeptinib Disables NLRP3 Inflammasome-Mediated IL-1β release and Pathways Required for Secretion of Inflammatory Cytokines IL-6 and TNFα. (Pubmed Central) - Jan 20, 2022
It also inhibits the kinases p38MAPK, ERK1/2, SAPK/JNK and activation of transcription factor NF-κBp65 with a concentration profile similar to its inhibition of cytokine release. Implications: The ability of luxeptinib to inhibit the NLRP3-mediated release of IL-1β and pathways involved in the release of IL-6 and TNFα at concentrations which are well-tolerated in patients makes it a candidate for the treatment of inflammatory diseases and inflammation-associated resistance in cancer.
- |||||||||| [VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) () - Sep 6, 2021 - Abstract #SOHO2021SOHO_385;
P1/2
We and others reported that preclinical efficacy of AZ5576, a selective inhibitor of CDK9, and its clinical congener AZD4573 in lymphoid tumors depended on rapid downmodulation of MCL1, BFL1, and MYC.19–21 CDK9 inhibition can increase efficacy of BH3-mimetics, but safety of this combination will need to be explored.22,23 CDK9 inhibitors in development, in addition to AZD4573, include VIP152, CYC065, and voruciclib...Navitoclax is a small-molecule inhibitor of BCL2, BCLX, and BCL2L2; however, its use in CLL has been plagued by thrombocytopenia.24 AZD4320 is an alternative agent that co-targets BCL2/X...ABBV-155, an antibody-drug conjugate targeting BCLX, where BCLX is being used as a payload to avoid “off-tumor” effects, demonstrated promise in solid tumor models.26 Finally, as many microenvironment-driven pro-survival pathways converge on NFB, leading to induction of chemokines, cell cycle regulators, and BCL2 family proteins themselves, this transcription factor continues to be an attractive target in CLL...When combined with ibrutinib in murine CLL models, VAY-736 produced prolonged survival compared with either therapy alone.28 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab), CD19 (tafasitamab), and others.29 As resistance to novel agents is becoming an unmet need in CLL, exploration of novel targets is of paramount importance...Multiple CDK inhibitors are currently being explored and have anti-tumor effects not restricted to MCL1 inhibition. CAR T cells and bi-specific antibodies have exceptional efficacy in lymphoid malignancies and thus are of high relevance in CLL.
- |||||||||| Journal: Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. (Pubmed Central) - Jul 28, 2021
These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib...Similarly, these TKIs reduced the percentage of activated integrin αβ on the platelet surface in response to CRP-XL, as determined by PAC-1 binding...Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
Phase classification: A Study of CG-806 in Patients With Relapsed or Refractory AML or Higher-Risk MDS (clinicaltrials.gov) - Jul 21, 2021
P1, N=80, Recruiting,
Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets. Phase classification: P1/2 --> P1
- |||||||||| [VIRTUAL] Assessment of the Effects of Syk and BTK Inhibitors on GPVI-mediated Platelet Signaling and Function (Room 3) - Jun 9, 2021 - Abstract #ISTH2021ISTH_1391;
Aims : Determine the effects of 12 TKIs (Bay 61-3606, R406/fostamatinib, entospletinib, TAK-659, ibrutinib, acalabrutinib, ONO-4059/tirabrutinib, AVL-292/spebrutinib, CG-806, BMS-935177, BMS-986195, fenebrutinib) on platelet functional responses...Platelets were stimulated and assessed for P-selectin exposure, PAC-1 binding, ATP secretion, adhesion on collagen and fibrinogen surfaces under static and physiological flow conditions, protein phosphorylation levels, and PI3K/tubulin colocalization to evaluate the effect of each inhibitor on platelet function...Fluorescence imaging of PI3K found co-localization with tubulin when untreated, but is disrupted in platelets treated with the selected TKIs. Conclusions : Clinically relevant TKIs targeting Syk and BTK inhibit platelet functional responses, but may differentially alter PI3K signaling and organization in an inhibitor class specific manner.
- |||||||||| luxeptinib (CG-806) / Aptose Biosci
[VIRTUAL] A PHASE 1A/B DOSE ESCALATION STUDY OF THE MUTATION AGNOSTIC FLT3/BTK INHIBITOR LUXEPTINIB (CG-806) IN PATIENTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA () - May 13, 2021 - Abstract #EHA2021EHA_1019;
P1/2
Luxeptinib simultaneously suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax...One heavily pretreated patient with relapsed AML with mutated NPM1, DNMT3A, and FLT3-ITD who had previously progressed after chemotherapy, alloSCT, and two FLT3 inhibitors (gilteritinib, crenolanib) demonstrated clinical anti-leukemic activity with a decrease in peripheral blood blasts from 93% to 10% during Cycle 1...Pharmacodynamic studies documented inhibition of FLT3 signaling pathway, and anti-leukemic activity has been observed in the setting of AML relapsed following therapy with multiple prior FLT3 inhibitors. Enrollment of patients with R/R AML continues and updated clinical data from this dose escalation study will be presented at the meeting.
- |||||||||| CG-806 / Aptose Biosci, CrystalGenomics
[VIRTUAL] Pharmacologic Inhibition of B Cell-Receptor-Associated Kinases with CG-806 Induces Apoptosis and Metabolic Reprogramming in Aggressive Non-Hodgkin Lymphoma (NHL) Models (Poster Hall (Virtual Meeting)) - Nov 5, 2020 - Abstract #ASH2020ASH_949;
While targeting BTK (ibrutinib, acalabrutinib) and PI3K (idelalisib, duvelisib) has shown efficacy in CLL, clinical responses fall short in aggressive NHL, necessitating the development of novel approaches to suppress BCR signaling...Consistent with the above observations, synergy was observed between CG-806 and inhibitors of metabolic enzymes (teleglenastat, perhexiline maleate) and BH3-mimetics targeting BCL2/X proteins (venetoclax, AZD4320)...BCL2 family proteins may be implicated in resistance to CG-806. These results provide rationale for further investigation of CG-806 in aggressive NHL.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, CG-806 / Aptose Biosci, CrystalGenomics
CG-806, a first-in-class FLT3/BTK inhibitor, and venetoclax synergize to inhibit cell proliferation and to induce apoptosis in aggressive B-cell lymphomas (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_2799;
P1
our study showed that CG-806 inhibited expression of the anti-apoptotic protein MCL1, overcame the effect of venetoclax-induced MCL1 and increased the level of proapoptotic BIM. While venetoclax produced no effect on MAPK signaling, CG-806 alone and in combination with venetoclax reduced p-MEK1/2, p-JNK and MYC in a cell line dependent manner.In conclusion, CG-806 inhibits driver and rescue pathways to directly and potently kill the aggressive B-cell lymphomas including DHL/THL/DEL and enhances the proapoptotic effect of venetoclax, thereby highlighting CG-806 as a promising candidate for the treatment of patients harboring unfavorable BCL2/MYC/BCL6 translocations and/or overexpression and supporting clinical development of CG-806 in patients with B-cell malignancies intolerant, resistant, or refractory to venetoclax.
- |||||||||| Synergistic Targeting of BTK and E-Selectin/CXCR4 in the Microenvironment of Mantle Cell Lymphomas (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5527;
Of note, blockade of CXCR4 or E-selectin with their antagonist plerixafor or GMI-1271, respectively, re-sensitized to CG-806-induced apoptosis in MCL cells, suggesting potential benefit of disrupting the crosstalk of TME and lymphoma cells in MCL therapy. Taken together, our findings may provide the basis for a new therapeutic strategy co-targeting TME, autophagy and BTK with the goal of overcoming the resistance to BTK-targeted therapy in MCL.
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