CHZ868 / Novartis, Memorial Sloan-Kettering Cancer Center - LARVOL DELTA

A Novel Approach Combining Type II JAK Inhibitor Chz-868 with Nutrient Restriction to Augment Cell Death in Philadelphia like Acute Lymphoblastic Leukemia (ASH 2024) - "Current clinical trials are assessing whether ruxolitinib, a type I JAK inhibitor, can enhance responses to chemotherapy in CRLF2-r acute leukemias. Conclusion : Efficacy of the type II JAK inhibitor CHZ-868 in CRLF2-r cells is enhanced by nutrient restriction. These results provide proof-of-concept for testing FMD as a diet-based approach to enhance TKI efficacy in Ph-like B-ALL patients."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2L11 • CRLF2 • MCL1

Selective JAK2 Pathway Inhibitor, CHZ868, Ameriorates Anti-Leukemic Functionaliry in CD19 CAR-T Cells (ASH 2024) - "However, the concurrent use of Janus kinase (JAK) 1/2 inhibitors, such as ruxolitinib, has been reported to reduce CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway...Furthermore, CHZ868 had a greater synergistic effect on CD19 CAR-T cells than fedratinib...In the in vivo stress test, the CD19 CAR-T cell group showed a modest anti-leukemic effect, which was enhanced when CD19 CAR-T was combined with CHZ868, as evidenced by the results of live tumor imaging and the prolonged survival of the mice. Conclusion : Our findings suggest that selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for the treatment of patients with resistant B-ALL, regardless of the JAK2 mutation status of their tumor cells."

CAR T-Cell Therapy • IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • CD19 • JAK1 • JAK3 • mTOR

Identifying Targeted Therapies for CBFA2T3-GLIS2 Acute Myeloid Leukemia (ASH 2023) - "Using a doxycycline-inducible knockout (KO) system, we validated JAK2 KO by western blot in three AML cell lines and cells from a patient-derived xenograft (PDX) harboring the fusion...Both the type I JAK2 inhibitor ruxolitinib and the type II JAK2 inhibitor CHZ868 exhibited strong activity in vitro in CBFA2T3-GLIS2 cell lines and PDX cells, many resistant to cytotoxic chemotherapy...Indeed, treatment with ruxolitinib and the MEK inhibitor trametinib exhibited a synergistic effect when used in combination in cell lines and PDX cells harboring the fusion in vitro, with in vivo testing as a next step...We demonstrated that JAK2 KO or small molecule inhibitors impaired cell viability and induced apoptosis in vitro, and JAK2 KO was highly efficacious in decreasing leukemia burden in vivo. Activation of the MAPK pathway renders resistance to JAK2 inhibitors and the combination of a JAK2 with MEK inhibitor is highly synergistic."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Pediatrics • CBFA2T3 • GLIS2 • NRAS • PTPRC

Identifying Targeted Therapies for CBFA2T3::GLIS2 Acute Myeloid Leukemia. (PubMed, Res Sq) - "Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and induced apoptosis with JAK2 KO. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2 positive AML models...Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CBFA2T3 • GLIS2 • NRAS

Selective JAK2 pathway inhibition enhances anti-leukemic functionality in CD19 CAR-T cells. (PubMed, Cancer Immunol Immunother) - "While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy against certain B-cell leukemias, such as Philadelphia chromosome-like acute lymphoblastic leukemia, the concurrent use of JAK1/2 inhibitors, such as ruxolitinib, has been implicated in reducing CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway. Transcriptomic analyses suggest that CHZ868 impedes CAR-T cell differentiation while preserving their proliferative capacity, a crucial factor in maintaining CAR-T cell functionality. Therefore, the selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for patients with resistant B-cell leukemias."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms. (PubMed, Front Oncol) - "Our study identifies JAK1 and JAK2 resistance variants against the type I JAK2 inhibitors ruxolitinib, fedratinib, and lestaurtinib. The sensitivity of these resistant variants towards the type II JAK2 inhibitor CHZ-868 indicates that this mode of type II JAK2 inhibition is a potential therapeutic approach against ruxolitinib refractory leukemia. This also proposes the development of potent and specific type II JAK2 inhibitors using ruxolitinib-resistance variants as a prototype."

Journal • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • CDC37 • JAK1 • STAT5 • STAT5AWqe

Development of resistance to type II JAK2 inhibitors in MPN depends on AXL kinase and is targetable. (PubMed, Clin Cancer Res) - "We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN."

Journal • Myeloproliferative Neoplasm • Oncology • AXL • STAT3

A Potential Mechanism for Major Adverse Cardiac Events Associated with JAK Inhibitors: JAK Inhibitor Withdrawal Causes Urokinase Release by Primed STAT Signaling (ACR Convergence 2023) - "Our findings suggest that ruxolitinib and baricitinib bind the active phosphorylated form of JAK and lead to a paradoxical cellular accumulation of functionally defective pJAK. Upon inhibitor withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, ultimately resulting in high levels of uPA. In contrast, CHZ868, which binds the inactive JAK kinase conformation, does not lead to pJAK accumulation, a pSTAT cascade, or uPA production."

Adverse events • Atherosclerosis • Dyslipidemia • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • CXCL9 • IFNG • PLAU

Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches. (PubMed, Blood Cancer Discov) - "Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling."

Journal • Myeloproliferative Neoplasm • Oncology

New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation. (PubMed, Cell Chem Biol) - "Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

Escape from Type II JAK2 Inhibition in MPN Depends on AXL/MAPK Activation and Is Targetable (ASH 2022) - "Based on pre-clinical data, novel type II JAK2 inhibitors as CHZ868 effectively stabilize inactive JAK2, reduce MPN clones and overcome resistance to ruxolitinib...Notably, dual JAK2 / AXL inhibition with CHZ868 / bemcentinib or CHZ868 / gilteritinib showed most pronounced inhibitory effects with IC50 similar to values seen in JAK inhibitor sensitive cells and effective induction of apoptosis...Combined JAK2 / MAPK inhibition with CHZ868 and trametinib significantly reduced BM infiltration by luciferase imaging and histology supporting that escape from type II JAK inhibition is dependent on AXL-MAPK activation. In summary, we report on a novel mechanism of AXL-MAPK driven escape from type II JAK2 inhibition which is targetable in vitro and in vivo. Our findings highlight that rationally designed combination therapy approaches can restore sensitivity to JAK inhibitor therapy in MPN, which may have potential implications for other malignant settings."

Myeloproliferative Neoplasm • Oncology • AXL • DUSP6 • FLT3 • PTPRC

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms (MPNs) (ASH 2022) - "Tamoxifen administration 12 weeks post-transplant to delete Jak2VF resulted in abrupt normalization of blood cell parameters, spleen weights, and serum pro-inflammatory cytokines, with a marked prolongation in overall survival (OS) compared to MPN control mice. Reduced peripheral blood (PB) and BM Cd45.2 mutant fraction was also observed, including within hematopoietic stem/progenitor cell (HSPC) compartments and to a greater degree than ruxolitinib (RUX) therapy. Notably, treatment with CHZ868, a type II JAKi, showed improvements in regard to hematocrit and spleen weight reduction on par with deletion, as well as significant reductions in BM HSPC mutant fractions, albeit to a lesser degree than with Jak2VF reversion (Figure 1B)...In sum, Jak2VF deletion abrogates MPN features, extends OS, and reduces mutant cell fraction with depletion of disease-sustaining MPN HSCs, either alone or in the setting of cooperating Tet2 loss. These data suggest JAK2VF mutant-selective..."

Myeloproliferative Neoplasm • Oncology • Transplantation • PTPRC • STAT5 • TET2 • TNFA • YBX1

The Second Generation Type II JAK2 Inhibitor, AJ1-10502, Demonstrates Enhanced Selectivity, Improved Therapeutic Efficacy and Reduced Mutant Cell Fraction Compared to Type I JAK2 Inhibitors in Models of Myeloproliferative Neoplasms (MPNs) (ASH 2022) - "Type I JAK inhibition (JAKi) represents a mainstay therapy for myelofibrosis and hydroxyurea-resistant high-risk polycythemia vera. Current type I JAKi, including ruxolitinib (RUX) and fedratinib, improve symptoms and outcomes in MPNs; however, JAK2VF allele burden remains essentially unchanged, and efficacy wanes over time...Kinome selectivity profiling of AJ1-10502 revealed potent JAK2 selectivity with minimal kinase cross-reactivity compared to CHZ868, including among other JAK family tyrosine kinases (Figure 1A)...Most importantly, AJ1-10502 results in superior reductions in PB and BM mutant cell fraction in vivo not observed with type I JAKi. These data demonstrate the preclinical utility of type II JAKi with AJ1-10502 and inform a path to clinical development of type II JAKi for MPN patients."

Clinical • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Transplantation • JAK2

Novel Drugs to Target JAK2 Rearrangements in Pediatric Acute Lymphoblastic Leukemia (ASH 2022) - "After 48h monotherapy treatment by CHZ868, we detected decreased cell viability (20-75% at IC50), which increased in the combination with dexamethasone...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased after ruxolitinib and chloroquine (autophagy inhibitor) combination (+20% vs ruxolitinib alone, p<0.01)...Instead, AT9283 (p<0.001 vs LCLs), Fedratinib (p<0.01 vs LCLs) and Gandotinib (p<0.05 vs LCLs) were found to be potent, specific, and non-toxic JAK2 inhibitors. Additionally, this extended screening led us to identify drugs, not belonging to JAK inhibitors, specific and non-toxic for rearranged JAK2 cohort, such as Birinapant (Smac mimetic), JQ1 (BRD4 inhibitor), Fludarabine (Chemotherapy) among the others. CHZ868 is a promising drug for the treatment of JAK2 fusions. Further studies will focus on effective and specific novel drugs found to be highly effective and specific on..."

Clinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • BRD4 • CASP3 • CD19 • CRLF2 • MME • P2RY8 • PAX5 • PDPK1 • STAT3 • STAT5 • ZEB2

Ajax Therapeutics Presents Preclinical Data on AJ1-10502, a Next Generation Type II JAK2 Inhibitor, at the American Society of Hematology Annual Meeting (Businesswire) - "Ajax Therapeutics... announced the presentation of preclinical data on the company’s next generation Type II JAK2 inhibitor, AJ1-10502, at a poster session held today at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans....The poster...highlights the improved efficacy and disease modifying features of Ajax’s Type II JAK2 inhibitor, AJ1-10502, when compared to the investigational, first generation Type II inhibitor, CHZ868, and the approved market-leading Type I inhibitor, ruxolitinib, in two different mouse models of MPNs."

Preclinical • Hematological Malignancies • Myeloproliferative Neoplasm • Oncology

JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Signaling Cascade in Minor Salivary Gland Mesenchymal Stromal Cells (ACR Convergence 2022) - "Our findings suggest that ruxolitinib and baricitinib, by binding the active phosphorylated form of JAK lead to a paradoxical cellular accumulation of functionally defective pJAK. Upon inhibitor withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade. In contrast, CHZ868, which binds the inactive JAK kinase conformation, does not lead to pJAK accumulation."

Hematological Malignancies • Lymphoma • Oncology • CXCL9 • IFNG • STAT5

IN VITRO AND IN VIVO EFFICACY OF A NOVEL KINASE INHIBITOR TARGETING JAK2 GENE REARRANGEMENTS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2022) - "In combination with dexamethasone, a further decrease of viability was observed...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased after ruxolitinib and chloroquine (autophagy inhibitor) combination(+20% vs ruxolitinib alone, p<0.01)...Conclusion CHZ868 is a promising drugfor the treatment of JAK2 fusionsBCP-ALL. Further studies will include combination with standard chemotherapy drugs, by reducing the intensity and toxicity of chemotherapy."

Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • CASP3 • CD19 • CRLF2 • MME • P2RY8 • PAX5 • PDPK1 • STAT3 • STAT5 • ZEB2

Targeting JAK2 Gene Rearrangements with a Novel Kinase Inhibitor in a Preclinical Model of Pediatric Acute Lymphoblastic Leukemia (ASH 2021) - "In combination with dexamethasone, we assessed a further decrease of viability between 10 to 95%...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased when ruxolitinib was given in combination with chloroquine, an autophagy inhibitor (+20% vs ruxolitinib alone, p<0.01)...CHZ868 is a promising candidate for treatment of BCP-ALL carrying JAK2 fusions, showing high efficacy and specificity, both ex vivo and in vivo . Further studies will include combination with standard chemotherapy drugs with the aim to maintain its efficacy by reducing the intensity and toxicity of chemotherapy."

Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • ATF7IP • CASP3 • CD19 • CRLF2 • JAK2 • MME • MPRIP • P2RY8 • PAX5 • STAT3 • STAT5 • TLE4

Troxerutin regulates HIF-1α by activating JAK2/STAT3 signaling to inhibit oxidative stress, inflammation, and apoptosis of cardiomyocytes induced by H O. (PubMed, Drug Dev Res) - "In addition, troxerutin improved viability and suppressed apoptosis, inflammation and oxidative stress of H O -induced cardiomyocytes, which was reversed by KC7F2 (a HIF-1α inhibitor) or CHZ868 (a JAK inhibitor). To sum up, troxerutin could regulate HIF-1α by activating JAK2/STAT3 signaling to inhibit oxidative stress, inflammation, and apoptosis of cardiomyocytes induced by H O ."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • HIF1A • PCR

Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia. (PubMed, NPJ Precis Oncol) - "Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL)...Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ATF7IP • JAK2

[VIRTUAL] Acquired mutations within the JAK2 kinase domain confer resistance to JAK inhibitors in in vitro models of acute lymphoblastic leukaemia driven by high-risk JAK2 fusion genes (LCC 2021) - "JAK2 p.G993A ATF7IP-JAK2 Ba/F3 cells were also resistant to the type-II JAK inhibitor, CHZ-868.ConclusionThe JAK2 ATP-binding site is susceptible to JAK inhibitor resistant mutations following ruxolitinib exposure, highlighting the importance of monitoring emergence of mutations within this region. Understanding mechanisms of ruxolitinib resistance has the potential to inform future drug design and development of therapeutic strategies for this high-risk cohort."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukaemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • JAK2 • JAK3

Therapeutic resistance to the novel JAK2 inhibitor CHZ868 in MPN is dependent on MEK-ERK activation and is targetable (SOHC 2020) - "Our data show that resistance to type II JAK2 inhibition in MPN relates to adaptive chromatin remodelling and is dependent on MEK/ERK activation responsive to trametinib. These findings indicate combined JAK2 and MEK inhibition as a therapeutic approach for MPN, particularly in resistance settings."

Clinical

[VIRTUAL] Acquired Mutations within the JAK2 Kinase Domain Confer Resistance to JAK Inhibitors in an in Vitro model of a High-Risk Acute Lymphoblastic Leukemia (ASH 2020) - "All mutations localized to the ATP/ruxolitinib binding site and conferred resistance to multiple type-I JAK inhibitors, including ruxolitinib, BMS-911543, and AZD-1480 (Table 1). JAK2 p.G993A ATF7IP-JAK2 Ba/F3 cells were also resistant to the type-II JAK inhibitor, CHZ-868, which binds in an allosteric site of JAK2 in addition to the ATP-binding site...The JAK2 p.G993A mutation was postulated to modulate the stability of a conserved domain. Understanding mechanisms of ruxolitinib resistance, as modelled here, has the potential to inform future drug design and the development therapeutic strategies for this high-risk cohort."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ATF7IP • JAK2 • JAK3 • STAT5

[VIRTUAL] Resistance to type II JAK2 inhibition can be overcome by MEK inhibition (DGHO 2020) - "JAK2 inhibitors as ruxolitinib are hampered by occurrence of resistance. Our data suggest that resistance to type II JAK2 inhibition with CHZ868 in MPN relates to adaptive chromatin remodeling mediating MEK/ERK activation. Resistance is dependent on MEK/ERK activation and is responsive to trametinib. These findings indicate combined JAK2 and MEK inhibition as a therapeutic approach for MPN, particularly in resistance settings."

Myeloproliferative Neoplasm • Oncology • JAK3 • STAT3

[VIRTUAL] Resistance to type II JAK2 inhibition can be overcome by MEK inhibition (DGHO 2020) - "JAK2 inhibitors as ruxolitinib are hampered by occurrence of resistance. Our data suggest that resistance to type II JAK2 inhibition with CHZ868 in MPN relates to adaptive chromatin remodeling mediating MEK/ERK activation. Resistance is dependent on MEK/ERK activation and is responsive to trametinib. These findings indicate combined JAK2 and MEK inhibition as a therapeutic approach for MPN, particularly in resistance settings."

Myeloproliferative Neoplasm • Oncology • JAK3 • STAT3