S55746 / Servier, Novartis, Ligand, HitGen - LARVOL DELTA

CLL drug resistance- A multifaceted mechanism (AACR 2025) - "Treatment of CLL cells from untreated patients with Bcl2is venetoclax, S55746, and LP-118 (Bcl2-Bclxli, Newave) showed increased sensitivity to the Bcl2/Bclxlis in HPNP but not in LPNP cells. These findings support increased resistance to apoptosis afforded by inhibiting Bcl2 for LPNP vs. HPNP-expressing CLL cells. Our future goals are to continue to understand the prognostic significance of the 4 genes with adverse clinical outcomes and to investigate how best to exploit the peculiar, enhanced sensitivity to Bcl2/Bclxlis found in the HPNP CLL cells."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2

Hydrogen/Deuterium Exchange and Protein Oxidative Footprinting with Mass Spectrometry Collectively Discriminate the Binding of Small-Molecule Therapeutics to Bcl-2. (PubMed, Anal Chem) - "Using drug-dependent perturbation as the experimental report, this combination of techniques more clearly differentiates the in-solution binding profiles of Venetoclax (ABT-199, GDC-0199-AbbVie and Genentech) and a drug candidate S55746 (Servier) to the apoptotic regulatory protein Bcl-2 than either technique alone. Both methods report the perturbation of some, but not all, residues mapped within 4 Å of the bound drugs in the crystal structures. Concordant characterization of backbone and side-chain accessibility will enhance our understanding of in-solution protein structure dynamics and protein-ligand interactions during drug discovery, development, and characterization, particularly when high-resolution structures are lacking."

Journal • BCL2

Identification of potent TMPRSS4 inhibitors through structural modeling and molecular dynamics simulations. (PubMed, Sci Rep) - "Therefore, this study aims to disover potential TMPRSS4 inhibitors that have better binding affinity than the approved inhibitors: 2-hydroxydiarylamide and tyroserleutide...Moreover, through a systematic analysis, MD simulations and MM-GBSA binding free energy calculations revealed that the best candidates Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 are highly stable drug candidates in complex with TMPRSS4, displaying low RMSD and RMSF values with strong binding stability. Among these compounds, Ergotamine showed the most favorable binding energy (-33.73 kcal/mol). Overall, our in silico results revealed that these compounds could act as potent TMPRSS4 inhibitors and need to be validated by future experimental studies."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • TMPRSS4

Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia. (PubMed, Int J Mol Sci) - "Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • EIF4E • EIF4EBP1

Role of purine metabolism in CLL cell pathobiology and CLL disease progression (AACR 2024) - "But PNP inhibitor forodesine did not show any significant killing in high vs low/no PNP group. When we treated CLL cells from untreated patients with Bcl2 inhibitors venetoclax, S55746 and LP-118 (Bcl-2/Bcl-xl inhibitor, Newave), CLL cells showed increasing sensitivity to the Bcl2 inhibitors associated with their PNP expression (high>low>no PNP)...These results indicate that active purine metabolism in CLL cells can contribute to differential novel agent drug responses of CLL patients. Future studies to understand the exact mechanism of how PNP relates to this differential drug sensitivity should be instructive in regard to alternate maneuvers to treat CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1

Novel Pi3kδ Inhibitor Roginolisib Synergizes with the Bcl-2 Inhibitor Venetoclax in Hematological Malignancies (ASH 2023) - "To further validate this finding, the combination of roginolisib with venetoclax or with another bcl-2 inhibitor S55746 was tested in a broad range of lymphoma cell lines including GRANTA519, JVM2, SP49 (MCL); FARAGE, TMD8 (diffuse large B cell lymphoma); MEC1 (chronic lymphocytic leukemia); MJ (cutaneous T cell lymphoma); and YT (NK lymphoma)...Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls...In addition, roginolisib synergized with venetoclax in lymphoma cell lines and CLL patient samples. Our data support extending this combination strategy to clinical trials in hematological malignancies."

IO biomarker • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • BCL2L1 • MCL1 • PIK3CD

Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia (ASH 2023) - "Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4E • EIF4EBP1

Emerging BCL 2 Inhibitors (SOHO 2023) - P1, P1/2, P1a/1b, P1b/2, P2 | "Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL..."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia • Waldenstrom Macroglobulinemia • BCL2L1

MIK665/S64315, a novel Mcl-1 inhibitor, in combination with Bcl-2 inhibitors exhibits strong synergistic antitumor activity in a range of hematologic malignancies (AACR 2019) - P1; "BH3 mimetics have been shown to bind to the BH3 binding groove of anti-apoptotic Bcl-2 family members and inhibit their function, resulting in apoptotic cell death, and one such BH3 mimetic, ABT-199 (venetoclax), has recently been approved for treatment of relapsed or refractory Chronic Lymphocytic Leukemia. In vivo, MIK665/S64315 and BCL201/S55746 combinations lead to complete and durable antitumor responses in many different xenograft models in mice and rats. Taken together, these data demonstrate that a combination of MIK665/S64315 and BCL201/S55746 provide strong therapeutic benefit over either monotherapy, and support a rationale for testing Mcl-1 and Bcl-2 inhibitor combinations in patients with hematological malignancies."

Combination therapy • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology

A NEW BCL-2 INHIBITOR (S55746/BCL201) AS MONOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY NON-HODGKIN LYMPHOMA: PRELIMINARY RESULTS OF THE FIRST-IN-HUMAN STUDY (ICML 2017) - P1; "S55746/BCL201 monotherapy showed acceptable safety and tolerability, and preliminary evidence of activity across the range of doses explored in various NHL subtypes, most notably DLBCL. Based on PK food interaction results, dose escalation is ongoing with S55746/BCL201 administered with food. Clinical trial information: NCT02920697."

Clinical • Monotherapy • Biosimilar • Diffuse Large B Cell Lymphoma • Indolent Lymphoma • Venous Thromboembolism

PRELIMINARY RESULTS FROM A PHASE 1 STUDY EXAMINING THE NOVEL BCL-2 INHIBITOR S55746/BCL201 AS SINGLE AGENT IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR HIGH RISK MYELODYSPLASTIC SYNDROME (EHA 2017) - P1; "Initial findings suggest that S55746/BCL201 has acceptable tolerability and clinical activity in advanced AML and MDS. Based on non-compartmental pharmacokinetic food interaction results from another study, demonstrating that S55746/BCL201 Cmax and AUC increased about 6-fold with food, dose escalation has started in patients with drug intake during a meal."

P1 data • Acute Myelogenous Leukemia • Biosimilar • Cardiovascular • Heart Failure • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Venous Thromboembolism

PRELIMINARY RESULTS OF S55746/BCL201 (A NEW BCL2 INHIBITOR) IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS AND EFFECT OF CALIBRATED MODERATE MEAL ON THE PHARMACOKINETICS (EHA 2017) - P1; "S55746/BCL201 monotherapy showed first signs of activity across the tested dose levels with an acceptable safety profile so far. Based on PK food interaction results, dose escalation in the fed state has started."

Clinical • Biosimilar • Chronic Lymphocytic Leukemia • Indolent Lymphoma • Venous Thromboembolism

Drug-repurposing against COVID-19 by targeting a key signaling pathway: An in silico study. (PubMed, Med Hypotheses) - "The three targets have the strongest affinity with three ligands-Akti-1/2, HSP990, S55746, respectively. In conclusion, this work provides three key elements to alleviate COVID-19 symptoms might be anti-inflammatory effects on SARs-CoV-2-infected lung cells."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • AKT1 • BCL2

[VIRTUAL] Role of the multi-drug resistance efflux pump MDR1 in conferring resistance to the BH3- mimetic compounds (LCC 2021) - "In chronic lymphocytic leukaemia, the pro-survival protein BCL2 is highly expressed and inhibiting BCL2 with a selective small molecule inhibitor venetoclax has proven to be highly effective...Unlike S63845 and its chemical analogs, the action of AMG-176, a distinct MCL1i, was not affected by overexpressing MDR1. Amongst the other BH3-mimetics we tested, the action of the BCL2 inhibitor S55746 was also compromised by MDR1 overexpression.Taken together, our findings suggest that MDR1 overactivity could potentially pose a barrier to the clinical efficacy of distinct classes of BH3-mimetics that target MCL1 (S63845 and its relatives) and BCL2 (S55746 and compounds of the same class). We conclude that other inhibitors of MCL1 or BCL2 should be considered in cancers with MDR1 overexpression."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • ABCB1 • BCL2L1

[VIRTUAL] Dynamic BH3 Profiling As Pharmacodynamic Biomarker for the Activity of BH3 Mimetics (ASH 2020) - "Using DBP and cell lines with defined dependency, we first showed that BH3 mimetics BCL201 (S55746) and S63845 are highly selective for Bcl-2 or Mcl-1, respectively. Exposure to BH3 mimetics causes changes in mitochondrial apoptotic signaling of T/B cells which are readily detectable by DBP. DBP with lymphoid cells may provide a robust PD biomarker for clinical trials testing BH3 mimetics, either as monotherapy or in combination with other agents."

Biomarker • IO Biomarker • PK/PD data • BCL2 • BCL2L1 • MCL1

[VIRTUAL] Acquired Mutations in BAX Confer Resistance to BH3 Mimetics in Acute Myeloid Leukemia (ASH 2020) - "Background: Recent randomized trials have demonstrated improvements in overall survival (OS) for the BCL-2 inhibitor venetoclax (VEN) in combination with azacitidine and low dose cytarabine in older unfit patients with AML...S63845 and S55746 were obtained from Servier/Novartis, A1155463 from G. Lessene (WEHI), venetoclax and cytarabine from Selleckchem... We identified the presence of BAX mutations in AML samples from patients progressing on VEN-containing regimens. We show that BAX, but not BAK loss in an AML cell line is associated with resistance to BH3-mimetic drug combinations resulting in reduced survival in AML xenograft models. In contrast, BAX deficiency does not impede the cytotoxic actions of conventional chemotherapy."

IO Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • BCL2L1

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. (PubMed, Blood Adv) - "Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option...Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate..."

Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1

[VIRTUAL] A NOVEL MECHANISM OF VENETOCLAX RESISTANCE IN ACUTE MYELOID LEUKEMIA: DELETION OF BAX (EHA 2020) - "It recently received accelerated US FDA approval for use in combination with hypomethylating agents or with low-dose cytarabine in elderly or unfit acute myeloid leukemia (AML) patients...The MV4-11 ABT-199R clones also demonstrated co-resistance to ABT-737 (BCL-2 and BCL-XL inhibitor), S63845 (MCL-1 inhibitor), and S55746 (BCL-2 inhibitor)...As a result of BAX gene deletion, the inhibitors of BCL-2, BCL-XL, and MCL-1 are rendered ineffective in inducing apoptosis. Alternative mechanisms of apoptosis induction need to be explored to overcome BAX deletion-induced resistance."

IO Biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BAX • BCL2L1

Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK-PD modeling and interspecies extrapolation. (PubMed, Invest New Drugs) - "Empirical approaches (ROC and oROC) gave similar predictive performances and seemed to overestimate the active S 55746 dose compared to mechanistic approaches, while strategies elaborated from semi-mechanistic concepts and PBPK-PD modelling did not seem to be invalidated by clinical efficacy data. Also, empirical methods only predict a single dose level for the subsequent clinical studies, whereas mechanism-based strategies are more informative about the dose response relationship, highlighting the potential interest of such approaches in drug development."

Journal • PK/PD data • Oncology

Prediction of human nonlinear pharmacokinetics of a new Bcl-2 inhibitor using PBPK modelling and interspecies extrapolation strategy. (PubMed, Drug Metab Dispos) - "Human PBPK predictions were within the 95% prediction interval for the 8 dose levels, taking into account both the nonlinear dose and time dependencies occurring in S 55746 kinetics. Thus, the proposed PK interspecies extrapolation strategy, based on preclinical and in vitro information and physiological assumptions, could be a useful tool for predicting human plasma concentrations at the early stage of drug development."

Journal • PK/PD data

Tumor Growth Inhibition modelling based on receptor occupancy and biomarker activity of a new Bcl-2 inhibitor in mice. (PubMed, J Pharmacol Exp Ther) - "The Bcl-2 inhibitor S 55746 ((S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is able to restore apoptosis functions impaired by tumorigenesis in mice...Tumor growth was inhibited by 50% when Casp was exceeded 13.8% of the time and C was exceeded 8.1% of the time per dosing. This semi-mechanistic approach, based on experimental mice data and in vitro parameters, provides an interesting tool to quantify or simulate the antitumor effects, and eventually, to plan phase 1 studies."

Biomarker • IO Biomarker • Journal

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1. (PubMed, ACS Omega) - "For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization."

Journal

IDENTIFICATION OF POTENT BH3-MIMETIC COMBINATIONS TARGETING PRO-SURVIVAL PATHWAYS IN HUMAN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ISEH 2019) - "...We report that dual BH3 mimetic targeting of BCL-2/MCL1 is strongly synergistic in SUPB15, BV173, MUTZ5 and MHHCALL4 B-ALL cell lines and was more effective than single BH3 mimetic combinations with dexamethasone (DXM) or TKIs (dasatinib/ruxolitinib)...BH3 mimetic combination therapy (S55746/S63845) compared favourably in Ph+ ALL cases to S55746 or S63845 used in combination with dasatinib...Simultaneous inhibition of BCL-2 and MCL1 represents a novel and effective approach for targeting Ph+, Ph- and Ph-like B-ALL without need for additional chemotherapy or kinase inhibition. Our results support the translational investigation of BH3-mimetic targeting of BCL-2 and MCL1 in the clinic."

Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. (PubMed, Leukemia) - "...Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents...Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy."

IO Biomarker • Journal

Targeting AML through apoptosis activation using Bcl-2/Mcl-1 or Bcl-2/Hdm2 inhibitor combination therapies (AACR 2019) - "Notably, lowering the dose of HDM201 by 4 fold from its most efficacious dose, resulted in a high degree of tumor regressions while mitigating the toxicity effects on platelets. Taken together, these data demonstrate that a combination of Bcl-2 inhibitor (BCL201/S55746 or venetoclax) with MIK665/S64315 or HDM201 provide therapeutic benefit over the monotherapy, and support a rationale for testing these apoptosis enhancing combination approaches in AML patients."

Combination therapy • IO Biomarker