Ask about this productRelated genes to: MAP4K1 Blocking Peptide
- Gene:
- MAP4K1 NIH gene
- Name:
- mitogen-activated protein kinase kinase kinase kinase 1
- Previous symbol:
- -
- Synonyms:
- HPK1
- Chromosome:
- 19q13.1-q13.4
- Locus Type:
- gene with protein product
- Date approved:
- 1999-09-07
- Date modifiied:
- 2014-11-18
Related products to: MAP4K1 Blocking Peptide
Related articles to: MAP4K1 Blocking Peptide
- The cytokines interleukin (IL)-22 and IL-17 are secreted by innate and adaptive immune cells to drive "type III" responses that protect against extracellular pathogens, promote mucosal barrier integrity, and foster microbiota homeostasis. However, dysregulation of IL-22 and/or IL-17 contributes to autoimmunity, chronic inflammation, and malignancy. Thus, a deeper understanding of mechanisms regulating type III cytokine production could provide new therapeutic targets for a spectrum of immune-mediated diseases. Toward this goal, we performed a genome-wide CRISPR inhibition (CRISPRi) screen to identify factors that regulate IL-22/IL-17 expression in a murine type III innate lymphoid cell (ILC3) model, MNK3, following stimulation with IL-23 and IL-1β. In addition to previously known regulators of type III cytokines, including IL-23 receptor components IL23R and IL12Rβ1, the screen identified a large set of new factors that either potentiate or attenuate expression of IL-22 and/or IL-17. A subset of these novel factors was chosen for validation, from which two were selected for further study. Knockdown of nuclear protein, SON, which binds both DNA and RNA, impaired expression of IL12Rβ1 at the levels of de novo transcription and RNA processing. The second, MAP4K1 (HPK1), is a serine/threonine kinase that is required for IL-22 but not IL-17 expression. Depletion of MAP4K1 in MNK3 also enhanced expression of the type I cytokine, IFN-γ, which was co-expressed with IL-17, a phenotype reminiscent of pathogenic Th17 cells. Together, results from the CRISPRi screen broaden our understanding of the factors involved in type III immune responses and offer new targets for modulating IL-22/17 expression. - Source: PubMed
Brown Rachel ADangel Andrew WSaini AnkitaCollins Patrick LColonna MarcoOltz Eugene M - Hematopoietic progenitor kinase 1 (HPK1) induces potent anti-tumor immunity in preclinical models by activating and recruiting T cells, B cells, and dendritic cells into the tumor microenvironment (TME). Here, we evaluate NDI-101150, a potent, selective HPK1 inhibitor, in a phase 1/2 trial as a monotherapy or in combination with pembrolizumab in patients with advanced solid tumors. The monotherapy maximum tolerated dose (MTD) is 150 mg once daily, and doses tested up to 100 mg once daily are combinable with pembrolizumab without reaching an MTD. In clear cell renal cell carcinoma, the investigator-assessed overall response rate with monotherapy treatment is 13.6%, including one complete response and two partial responses, with a clinical benefit rate of 27.3% and a disease control rate of 54.5%. Pharmacodynamic analyses show pharmacodynamic biomarker phospho-SLP76 inhibition and increased activated CD8 T cells and dendritic cells in the TME, supporting continued development (clinical registration number NCT05128487). - Source: PubMed
Publication date: 2026/05/06
Braun David ANoel Marcus SMoy Ryan HDemel KurtGutierrez MartinSharma SunilHussain ArifGadgeel ShirishPeguero JulioChoueiri Toni KEmamekhoo HamidVan Tine BrianBalaraman RamaElliott GiNellNath SritamaDaigle Scott RKumar PavanScheuber AnitaSommerhalder David - Immunotherapy has revolutionized cancer treatment, offering new hope for many patients. However, while some individuals show remarkable responses, the overall success rate remains limited. This has spurred interest in combination therapies, particularly with established treatments like radiation therapy (RT), to improve outcomes. RT is a cornerstone of cancer therapy and known to influence the immune landscape, yet a systematic characterization of its effects on tumor-infiltrating leukocytes (TILs) and a rationale-based therapy is still lacking. In this study, we employed a diverse set of pre-clinical syngeneic murine tumor models with varying immune profiles to investigate the immunological impact of tumor targeted RT. We observed that immunologically 'hot' tumors showed stronger tumor growth inhibition (TGI) after RT compared to 'cold' tumors. Additionally, RT induced both pro- and anti-inflammatory shifts within the tumor immune microenvironment. Importantly, RT led to an intra-tumoral increase in proliferating CD8 T cells, while the population of proliferating macrophages was notably reduced. To identify immune-modulatory pathways that shape the response to RT across different tumor immune contexts, we tested RT in HPK1 (Hematopoietic Progenitor Kinase 1) and STING (Stimulator of Interferon Genes) deficient mice. These experiments revealed that STING deficiency compromises TGI in tumors with a high baseline population of myeloid cells expressing an interferon response signature. Moreover, we identified a synergistic effect on survival in tumor-bearing mice when combining HPK1 deficiency with RT. Thus, RT promotes expansion of cytotoxic T cells while limiting macrophage proliferation, with therapeutic outcomes strongly influenced by STING and HPK1 pathways. Collectively, these results highlight the complex interplay between RT, tumor immune microenvironment and response to therapy, offering potential avenues for novel therapeutic combinations. - Source: PubMed
Publication date: 2026/03/27
Wirtz TristanLee CatherineRam SripadXie TaoMojtahedzadeh SepidehStreiner NicoleNoorbehesht KavonManzuk Lisa KRohner AllisonCabral EdwardBonato ViniciusAffolter TimothyKraus ManfredDillon ChristopherGiddabasappa Anand - Currently, efficient exploration of biologically relevant chemical space remains a significant challenge in lead discovery. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell activation and a high-priority target for cancer immunotherapy. Herein, we report an integrated combinatorial chemistry-biological assay approach to accelerate lead identification for HPK1. First, an in-house HPK1 inhibitor library was fragmented and recombined , followed by molecular docking, yielding preferred fragments. Then, selected fragments were assembled in a microplate, and the resulting compounds were used directly to perform biological assays, leading to the identification of lead compound . Guided by four series of structure-activity relationship studies, our efforts afforded the optimized compound (HPK1 IC = 1.7 nM). Compound suppressed SLP76 phosphorylation, enhanced IL-2 release in the cell, and displayed low CYP/hERG risk. Moreover, compound demonstrated potent antitumor efficacy in both mouse models, which highlighted its potential as a preclinical immunotherapy candidate. - Source: PubMed
Publication date: 2026/03/13
Duan YipingHe ChenGuo ZhichaoSun KaiZheng TiandongLu YangZhang BaixueZhong WenyiRen YansongLiu JieXu ShengtaoXu Jinyi - Hematopoietic progenitor kinase 1 (HPK1) has emerged as a compelling target for tumor immunotherapy due to its pivotal role in regulating key cellular processes, including survival, migration, apoptosis, and autophagy. In this comprehensive study, we characterized the pharmacological profile of a novel HPK1 inhibitor HDM2004 (compound 37). Through systematic structure-activity relationship (SAR) optimization, HDM2004 was identified as a highly potent HPK1 inhibitor (IC = 1.89 nM) with >30-fold selectivity over the closely related kinase GLK. The compound exhibits favorable drug-like properties, including high metabolic stability (human liver microsomal half-life >300 min) and minimal inhibition of cytochrome P450 enzymes (IC > 10 μM). Pharmacokinetic (PK) studies across multiple species demonstrated dose-proportional exposure, excellent oral bioavailability, and favorable tissue distribution. Importantly, HDM2004 displayed synergistic antitumor activity when combined with PD-L1 blockade in syngeneic mouse models, while maintaining an acceptable safety profile. Collectively, these data support HDM2004 as a promising preclinical candidate for combination cancer immunotherapy. - Source: PubMed
Publication date: 2026/02/20
Zhang ZhiminHuang MinhaoE JingwenZhang ZhipingDeng TaoYang YachengSun YinaZou JunjieZhang XiaohuaChen TingniLiu Dongzhou