BMS-911543 / BMS - LARVOL DELTA

Disrupting a new NFkB-IL-6-JAK2-STAT cascade with novel NFkB inhibitors reduces primary myelofibrosis growth (ASH 2025) - "The therapeutic and preventiveeffects of Ixazomib and emetine were evaluated in HEL-engrafted nude mice by assessing tumorformation, development, and underlying mechanisms using Western blot, H&E and IHC staining. Short-term JAKi (BMS-911543, ruxolitinib) exposure altered JAK2 phosphorylation, increasingTyr1008 phosphorylation and decreasing Tyr221, Tyr570, and STAT5 phosphorylation. We discovered that STAT inactivation independently predicts improved outcomes in PMFand that NFκB hyperactivity holds particular significance for PMF compared to other MPN subtypes. Weidentified a NFκB-IL-6-JAK2-STAT axis in regulating PMF growth regardless of JAK2V617F status. TargetingNFκB with novel inhibitors Ixazomib and emetine disrupts the NFκB-IL-6-JAK2-STAT axis, suppressing PMFgrowth and offering potential therapeutic alternatives to overcome current JAKi limitations."

Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • CASP3 • IL6 • JAK2 • STAT3 • STAT5

Outcome of Splenectomy in JAK2 Inhibitor Treated Patients with Myelofibrosis: A Mayo Clinic Experience in 34 Consecutive Cases (ASH 2024) - "JAKi included ruxolitinib (n=27), momelotinib (n=5), pacritinib (n=3), fedratinib (n=3), and BMS-911543 JAKi (n=5). In addition, among 5 non-transplanted patients with baseline thrombocytopenia ( 100 x 109/L (median; 170 x 109/L, range : 119-279 x 109/L) within 3 months post-procedure.Conclusions : Splenectomy following JAKi-resistant or intolerant MF is associated with improvement of transfusion-dependent anemia (46% response), resolution of severe thrombocytopenia (80%), and may allow for successful transition to ASCT (35%). However, the procedure is associated with significant perioperative complications occurring in the majority of patients and underscores the need for future collaborative studies to develop selection criteria and evaluate alternative treatment modalities."

Clinical • Anemia • Cardiovascular • Hematological Disorders • Infectious Disease • Myelofibrosis • Renal Disease • Respiratory Diseases • Thrombocytopenia • Thrombosis • ASXL1 • CALR • SRSF2

Novel janus-kinase (JAK) inhibitors in myelofibrosis. (PubMed, Expert Opin Investig Drugs) - "This review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate...In patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS)...The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs."

Journal • Review • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Determinants of Survival and Retrospective Comparisons in 183 Clinical Trial Patients with Myelofibrosis Treated with Ruxolitinib, Fedratinib, Momelotinib, or BMS-911543 JAK2 Inhibitor between 2007 and 2013 (ASH 2022) - P1, P1/2, P2 | "Introduction Currently, ruxolitinib, fedratinib and pacritinib are three FDA-approved JAK2 inhibitors used for palliation of splenomegaly and constitutional symptoms in patients with myelofibrosis. Survival was not influenced by type of JAK2 inhibitor but was superior in spleen and anemia responders and in the absence of SRSF2 mutations. In addition, fedratinib use and absence of ASXL1 mutations predicted spleen response, while SRSF2 mutations correlated with anemia response."

Retrospective data • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • Transplantation • ASXL1 • CALR • IDH1 • IDH2 • SRSF2

Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor. (PubMed, Blood Cancer J) - "Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival."

Journal • Retrospective data • Bone Marrow Transplantation • Hematological Disorders • Myelofibrosis • Transplantation • ASXL1 • CALR • SRSF2

Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor (Nature, Blood Cancer J) - "Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31)....5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01)."

Retrospective data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor (Nature, Blood Cancer J) - "Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31)....5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01)."

Retrospective data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes. (PubMed, Pharmacol Res) - "This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy."

Journal • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • FABP5 • IL22 • STAT3

Insulin-like growth factor 1 induces a reparative neutrophil phenotype. (PubMed, FASEB J) - "Additionally, Jak1/2/3/Tyk2 was inhibited with pharmacological inhibitors (InSolution Jak Inhibitor I, Ruxolitinib, BMS-911543). In conclusion, these findings indicate that IGF1 is able to polarize neutrophils to a reparative N2-like phenotype most likely via the non-canonical Jak2-Stat6 axis, comparable to that induced by the classical M2/N2 polarizer IL-4. Additionally, IGF1 is able to reverse proinflammatory mechanisms."

Journal • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Heart Failure • Myocardial Infarction • AKT1 • AKT2 • IFNG • IGF1 • IL12A • IL4 • JAK1 • TNFA • TYK2

JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis. (PubMed, J Allergy Clin Immunol) - "Our results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of AD patients."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pruritus • JAK1

[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

C-H Arylation in the Formation of a Complex Pyrrolopyridine, the Commercial Synthesis of the Potent JAK2 Inhibitor, BMS-911543. (PubMed, J Org Chem) - "During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest-linear sequence) from readily available materials."

Journal

Multiple Ascending Dose of BMS-911543 (clinicaltrials.gov) - P1/2; N=98; Terminated; Sponsor: Bristol-Myers Squibb; Completed ➔ Terminated; Due to portfolio/business decisions by the sponsor

Clinical • Trial termination