Potent PI3Kδ Inhibitor Research Articles

Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

Preclinical pharmacokinetic characterization of amdizalisib, a novel PI3Kδ inhibitor for the treatment of hematological malignancies.

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors.

The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 μM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury.

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. (S)-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of (S)-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, (S)-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blottingand flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) atsubnanomolar levelsand had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in agood concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1, A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2-d]pyrimidine can facilitate thedesignofnovel potent and selective PI3Kδ inhibitors.

Discovery of potent and selective PI3Kδ inhibitors bearing amino acid fragments

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and β. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.

223 (PB103) - Non-ATP competitive inhibition of PI3Kδ with IOA-244 shows anti-lymphoma activity

Background: Activation of PI3 K signaling, mainly mediated via PI3Kδ,is a fundamental signaling cascade in lymphomas (Tarantelli et al, 2021). IOA-244 (IOA) is a highly selective and potent PI3Kδ inhibitor with atypical non-ATP competitive activity (Johnson et al, 2019) compared to FDA-approved PI3 K inhibitors idelalisib, copanlisib and duvelisib. IOA is in phase 1 as an immunomodulatory agent for patients with melanoma, mesothelioma, non-small cell lung cancer, myelofibrosis, and follicular and peripheral T cell lymphoma (TCL) as a single agent or in combination (NCT04328844).

Abstract 5453: FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies

Abstract Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway plays critical roles in cell growth, differentiation, motility, survival, and intracellular trafficking, and is one of the most frequently dysregulated pathways in human cancers including B-cell malignancies. There are 3 classes of PI3K, among which Class I PI3Ks including PI3Kα, β, γ, and δ isoforms are the mostly studied and plays key roles in physiological functions. PI3Kα has a role in insulin-dependent signaling, PI3Kβ functions in platelet aggregation, thrombosis and insulin signaling, and PI3Kγ/δ are expressed mainly in leukocytes and regulate lymphocyte activation, mast cell degranulation, and chemotaxis. Early PI3K inhibitors such as idelalisib are effective against B-cell malignancies such as chronic lymphocytic leukemia, but their clinical use is largely limited due to intolerable toxicities. More selective PI3Kδ inhibitors such as umbralisib (TGR-1202) demonstrates improved clinical efficacy and safety profile compared to current standard of care and was recently approved as a monotherapy for follicular lymphoma and marginal zone lymphoma. However, there is still unmet medical need for novel PI3Kδ inhibitors with improved safety profile and better efficacy to be used as monotherapy and in suitable combination strategies. Here we introduce FCN-289, a novel and oral next-generation PI3Kδ inhibitor. FCN-289 demonstrates potent kinase activity against PI3Kδ with single-digit nanomolar IC50 and remarkably improved selectivity over other PI3K isoforms compared with TGR-1202. FCN-289 exhibits significant anti-proliferating activity against various human diffuse large B-cell lymphoma (DLBCL)-derived cancer cell lines (OCI-LY10, TMD-8 and WSU-NHL) with superior activity compared with TGR-1202. Consistently, FCN-289 shows dose-dependent anti-tumor growth activity superior to that of TGR-1202 at the same and higher dose in TMD-8 DLBCL xenograft models. FCN-289 shows significantly improved anti-tumor activity when combined with BTK inhibitor ibrutinib in TMD-8 and OCI-LY10 DLBCL xenograft models. In non-clinical settings, FCN-289 exhibits good pharmacokinetic (PK) and safety properties with shorter Tmax and higher bioavailability in both rats and dogs, higher exposure in rats, improved CYP450 inhibition profile, and less plasma protein bound ratio compared with TGR-1202.Together, FCN-289 is a novel PI3Kδ inhibitor that possesses more potent in vitro and in vivo anti-cancer activities in B-cell malignancies-derived models with improved selectivity against other PI3K isoforms compared with TGR-1202. Combination with ibrutinib further improves anti-tumor activity compared with monotherapy. FCN-289 shows favorable PK and safety profiles compared with TGR-1202. Our findings highlight the therapeutic potential of FCN-289 as a novel targeted approach as monotherapy or in combination for treating B-cell malignancies. Citation Format: Shu Lin, Zuwen Zhou, Rui Tan, Hua Xu, Huajie Zhang, Weipeng Zhang, Ling Chen, Lijun Yang, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5453.

Abstract 5454: Amdizalisib (HMPL-689), a highly selective PI3Kδ inhibitor, exhibits potent anti-tumor activity in pre-clinical B-cell lymphoma models

Abstract Background: The delta isoform of PI3K (PI3Kδ) plays an important role in B-cell development and function by mediating the signaling of key receptors on B cells. Aberrant activation of PI3Kδ signaling pathway promotes the survival and proliferation of malignant B cells, making selective inhibition of this isoform a promising therapeutic approach for the treatment of B cell malignances. Amdizalisib (HMPL-689, Amdiz), discovered and being currently developed in a pivotal phase II clinical trial (NCT04849351) by HUTCHMED, is a highly potent and selective PI3Kδ inhibitor. Based on encouraging clinical data from the phase Ib study (2021 ESMO, abstract# 8330), Amdiz is a designated breakthrough therapy in China for treatment of relapsed and refractory follicular lymphoma. Herein, we report the pre-clinical anti-tumor activity of Amdiz. Methods: Kinase activity was measured by Transcreener™ Fluorescence Polarization assay. The kinome selectivity profile of Amdiz was evaluated in Eurofins KinaseProfiler™ panel containing 323 kinases. Cell based phosphorylation of AKT was determined by using Acumen Explorer system. CD63 expression in basophils was evaluated by FACS assay. Inhibitory effects of Amdiz alone or in combination with other agents on cell viability were investigated in a panel of B cell lymphoma cell lines by CellTiter-Glo luminescent or CCK-8 assay. The ability of Amdiz to inhibit the activation of B cells in animals was evaluated in naïve rats using an ex vivo assay, and B cell activation was determined by evaluating CD86 expression using FACS analysis. Human B cell lymphoma cell line derived xenograft models were used to determine the anti-tumor activity of Amdiz in combination with other agents such as rituximab, BTK inhibitor, and venetoclax. Results: Amdiz is a highly selective inhibitor of PI3Kδ, showing more than 250-fold selectivity over other PI3K isoforms and no significant inhibition over other 319 protein kinases at the concentration of 1 µM. Amdiz potently inhibited PI3Kδ in biochemical, cellular and human whole blood assays with IC50s ranging from 0.8-3 nM. Its inhibitory effects on cell viability were also evaluated in a panel of B -cell lymphoma cell lines. Results showed that Amdiz potently inhibited cell survival with IC50s from 0.005 to 5 μM. Amdiz showed a long-lasting and strong inhibition on B cell activation in a rat pharmacodynamics (PD) study at a dose as low as 0.1 mg/kg. Moreover, Amdiz significantly improved anti-tumor activity of standard-of-care agents as well as targeted agents in multiple B-cell lymphoma models both in vitro and in vivo. Conclusion: Amdiz is a highly potent and selective PI3Kδ inhibitor with strong activity against B-cell lymphoma in pre-clinical studies, supporting clinical evaluation as either a single agent or in combination with other therapeutic agents for the treatment of B-cell malignancies. Citation Format: Jia Hu, Jianhan Wang, Xiaoming Dai, Jianlin He, Junqing Liang, Ying Yu, Juntao Yu, Na Yang, Linfang Wang, Yu Cai, Xiong Li, Weiguo Qing, Yongxin Ren, Weiguo Su. Amdizalisib (HMPL-689), a highly selective PI3Kδ inhibitor, exhibits potent anti-tumor activity in pre-clinical B-cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5454.

Design and Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for the Treatment of B-Cell Malignancies.

Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.

Potent and Selective PI3Kδ Inhibitors for the Treatment of Hepatocellular Carcinoma

Key words hepatocellular carcinoma - PI3Kδ inhibitors - Ullmann coupling

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.

Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation.

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). Invitro studies revealed that FD223 displays high potency (IC50=1nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, invivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ inhibitor for the treatment of leukemia such as AML.

The PI3Kδ inhibitor parsaclisib ameliorates pathology and reduces autoantibody formation in preclinical models of systemic lupus erythematosus and Sjӧgren’s syndrome

Dysregulation of phosphoinositide 3-kinase δ (PI3Kδ) signaling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases. Parsaclisib (INCB050465) represents a potent and selective PI3Kδ inhibitor, which is being clinically investigated for treatment of autoimmune hemolytic anemia and hematological malignancies. We characterized the potential of parsaclisib to ameliorate autoimmune mechanisms implicated in the pathophysiology of systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Spontaneous mouse models of SLE and SS were utilized to elucidate the efficacy of orally administered parsaclisib on autoreactive B-cell-mediated antibody-driven disease. Parsaclisib significantly reduced disease symptoms and pathology in three distinct mouse models of SLE. Parsaclisib effectively preserved renal function as measured by glomerular filtration rate, abrogated histopathological evidence of nephritis, modulated discrete immune cell subsets, and decreased anti-dsDNA antibody level. Furthermore, parsaclisib demonstrated efficacy in two spontaneous mouse models of SS. Oral parsaclisib treatment ameliorated the severity of salivary gland inflammation and reduced circulating levels of autoantibodies. Parsaclisib mediated improvement of salivary gland inflammation coincided with reduced B-cell activating cytokine (BAFF) in saliva. Transcriptomic analysis of kidney and salivary gland tissues revealed a downregulation in inflammatory gene expression consistent with PI3Kδ pathway inhibition. Parsaclisib reduced autoreactive B-cells and autoantibody levels, and significantly improved nephritis and salivary gland inflammation. These data provide the scientific rationale for PI3Kδ inhibition as a therapeutic strategy for treatment of B-cell-mediated antibody-driven autoimmune diseases.

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Exposure-Response of Idelalisib Administered in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Chronic Lymphocytic Leukemi

Background: Idelalisib (IDELA) is a potent and selective PI3Kδ inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) (in combination with rituximab) and relapsed indolent non-Hodgkin lymphoma (iNHL) subtypes, follicular lymphoma, and small-cell lymphocytic lymphoma. The relationship between plasma exposures of IDELA and clinical efficacy and safety were evaluated in relapsed/refractory CLL subjects following administration of IDELA 150 mg twice daily (BID) in combination with bendamustine (B) and rituximab (R; Study GS-US-312-0115).Methods: IDELA peak and trough plasma samples were collected every 4 weeks (up to 24 weeks) starting at baseline. Data for safety and efficacy endpoints were collected every 2 and 12 weeks, respectively. IDELA plasma exposures (Cmax, AUCtau, and Ctau) were generated using a previously developed population pharmacokinetic (PK) model (Jin F, et al. CCP . 77: 89-98, 2016). Efficacy and safety data from the phase 3, randomized, double-blind, placebo-controlled study (GS-US-312-0115) were included in the PK/pharmacodynamics (PD) analyses. Efficacy endpoints, including best overall response rate (BOR), duration of response (DOR), progression-free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR), were evaluated against IDELA exposures (AUCtau and Ctau). Safety endpoints, including Grade 3 or 4 adverse events of neutropenia, skin rash, infection, pneumonia, pneumonitis, diarrhea, colitis, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, were evaluated versus IDELA exposures (AUCtau and Cmax). The relationship between average daily dose of IDELA versus exposures (AUCtau and Cmax) was also evaluated. Statistical analysis (such as Kaplan-Meier survival analysis, Cox proportional hazard model, or logistic regression) was conducted for selected efficacy and safety endpoints.Results: Median IDELA exposures were similar in subjects who achieved an objective response (complete response or partial response) and subjects who did not respond (stable disease or progressive disease) and across the 4 response categories (p=0.68; Table 1). As IDELA exposure increased over quartiles, there was no clear trend of prolonged DOR (p=0.50), PFS (p=0.69), or change in SPD. No relationship between LNR (responder versus non-responder) and IDELA exposure was observed. No association was observed between IDELA exposure vs incidence of neutropenia (p=0.35), diarrhea (p=0.78), pneumonia (p³0.12), colitis (p=0.62), AST or ALT elevation (p=0.45), skin rash, and pneumonitis. An increase in the incidence of Grade 3 or 4 infections with higher IDELA exposures was observed (p=0.021). Overall, IDELA in combination with BR was well tolerated, as indicated by the comparable average daily doses (~300 mg) administered across quartiles of IDELA exposure.Conclusions: No exposure-response relationships were observed for efficacy or safety (except infections) endpoints at IDELA 150 mg BID. These results are consistent with the previously observed IDELA exposure-response relationship in subjects with CLL (in combination with rituximab or ofatumumab) and iNHL. Overall, this analysis supports IDELA 150 mg BID in combination with BR for the treatment of relapsed CLL in patients who are fit for immunochemotherapy. [Display omitted] DisclosuresDaryani:Gilead Sciences, Inc.: Employment, Equity Ownership. Sharma:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead: Employment, Equity Ownership. Silverman:Gilead Sciences, Inc.: Employment, Equity Ownership. Adewoye:Gilead Sciences, Inc.: Employment, Equity Ownership. Mathias:Gilead Sciences, Inc.: Employment, Equity Ownership.

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases.

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.

Efficacy and safety of duvelisib, a phosphoinositide 3 kinase (PI3K) δ and γ inhibitor, in Chinese patients (pts) with relapsed/refractory follicular lymphoma (R/R FL): A single-arm, open-label, multicenter, phase Ⅱ clinical trial.

e19532 Background: Follicular lymphoma (FL) is a common type of non-Hodgkin’s lymphoma with high rates of recurrence. The conventional therapy for R/R FL is not curative. Duvelisib is a potent inhibitor of both PI3K-δ and PI3K-γ that has been approved by the FDA for pts with R/R chronic lymphocytic leukemia, R/R small lymphocytic lymphoma, and R/R FL after at least two prior therapies. The current study aimed to evaluate the efficacy and safety of duvelisib in Chinese pts with R/R FL after at least two prior therapies. The current study aimed to evaluate the efficacy and safety of duvelisib in Chinese pts with R/R FL after at least two prior therapies. Methods: This was a single-arm, open-label, multi-center, phase Ⅱ clinical trial. Adult pts (ECOG ≤ 2) with histologically confirmed FL who have progressed on or relapsed after at least two prior therapies (at least one prior therapy was rituximab-contained regimen) were recruited. The main exclusion criteria were pts with grade 3b FL or those whose condition showed a propensity to transform to aggressive lymphoma. Duvelisib 25 mg was administered orally, twice daily in a 28-day cycle (max. 12 cycles) until disease progression, intolerable toxicity, death, or withdrawal. The primary endpoint was ORR as determined by Independent Review Committee (IRC) based on the revised International Working Group response criteria for Malignant Lymphoma (IWG 2007). Secondary endpoints included ORR reported by investigators as per IWG 2007; ORR reported by IRC and investigators as per Lugano 2014 criteria; DOR; PFS; OS; TTR; and safety outcomes. Results: 23 pts (22 R/R FL and 1 diffuse large B cell lymphoma) were enrolled and included in efficacy and safety analyses (last patient first dose was on Jun 30, 2020). The median age was 49 (range, 31-70) years, and 30% were females. At the data cut-off date (Dec 30, 2020), as per IWG 2007, the ORR reported by IRC was 83%, with a best response of 6 complete responses (CR) and 13 partial responses (PR); and the ORR reported by investigators was 78%, with a best response of 18 PR. As per Lugano 2014 criteria, the ORR was 83% by IRC (7 CR + 12 PR) and 78% by investigators (2 CR + 16 PR). Median DOR, PFS, and OS have not been reached. Median TTR was 1.8 (range, 1.6-5.5) months by IRC. Treatment-related adverse events (TRAEs) of any grade occurred in 21 (91%) of 23 pts, in which 12 (52%) were ≥ grade 3. The most common ( > 20%) TRAEs were neutropenia (16, 70%), increased alanine aminotransferase (11, 48%), increased aspartate aminotransferase (10, 44%), leukopenia (7, 30%), thrombocytopenia (6, 26%), increased lactate dehydrogenase (5, 22%), and rash (5, 22%). Conclusions: Duvelisib yielded impressive anti-tumor activity with manageable safety profiles in Chinese R/R FL pts and could be a compelling treatment option in this setting. Clinical trial information: NCT04707079.