Inhibitors of immuno-oncology target HPK1 – a patent review (2016 to 2020)

Linney, Ian D.; Kaila, Neelu

doi:10.1080/13543776.2021.1924671

Cited by 22 publications

(12 citation statements)

References 38 publications

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“…The ndings from glioma cell syngeneic studies suggested that inhibiting HPK1 kinase function enhanced tumor immune surveillance and might provide a synergistic effect when combined with checkpoint blockade [10,31]. Pharmacological HPK1 inhibitor was desirable to be applied for therapeutic implications [11,32]. Here we showed that HPK1 inhibitor can ameliorate the e cacy of anti-PD-1 immunotherapy and would be a combined therapy strategies for NHL.…”

Section: Discussionmentioning

confidence: 67%

HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy in Non-Hodgkin lymphoma

Yang

Zhao

Chen

et al. 2022

Preprint

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Anti-PD-1 immunotherapy has been widely applied in patients with some types of lymphomas. The classical Hodgkin's lymphoma is highly sensitive to immunotherapy but Non-Hodgkin's lymphoma (NHL) is not good response. Therefore, it is valuable to optimize PD-1 blockade treatment in NHL patients. Studies indicated that HPK1 suppressed T cells and reduced the anti-tumor immunity. Therefore, HPK1 inhibitor may restore and elicit antitumor immune responses and is a promising candidate drug target for cancer immunotherapy. We initially explored the Gene Expression Profile Interactive Analysis (GEPIA) databases and it predicted that HPK1 expression increased in DLBCL and was associated with NLRP3. We investigated whether the HPK1 inhibitor could enhance tumor response to anti-PD-1 immunotherapy in NHL and the association between HPK1 and NLRP3. Employing shHPK1 and inhibitor, our study demonstrated that HPK1 inhibitor increased the anti-PD-1 mediated T cell cytotoxicity on BJAB and WSU-DLCL2 co-cultured with peripheral blood mononuclear cells (PBMCs). HPK1 inhibitor increased PD-1, PD-L1, Bax, p53 and NK-kB but decreased NLRP3. These indicated that HPK1 inhibitor was associated with apoptosis and NLRP3 inflammasome pathway in anti-PD-1 mediated T cell cytotoxicity. Our data also demonstrated that HPK1 inhibitor enhanced the efficiency of anti-PD-1 immunotherapy on NHL in in vivo zebrafish xenograft models. In summary, this study provided the evidence that HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy for NHL by promoting apoptosis and blocking NLRP3 pathway. This provides a potential therapeutic option for NHL with combination HPK1 inhibitor and anti-PD-1 immunotherapy.

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Section: Discussionmentioning

confidence: 67%

HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy in Non-Hodgkin lymphoma

Yang

Zhao

Chen

et al. 2022

Preprint

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“…18,19 In preclinical syngeneic tumor models, HPK1 inhibition was found to promote tumor immune surveillance and demonstrated a synergistic effect when combined with checkpoint blockade. 20 Given the compelling evidence, it has been proposed that HPK1 is a highly desirable target in cancer immunotherapy. 21,22 HPK1 and GLK (MAP4K3) are phylogenetically close and structurally similar members of the MAP4K family, sharing high homology and similarity in sequences and structures.…”

Section: ■ Introductionmentioning

confidence: 99%

“…22,25 This suggested that achieving selectivity over GLK will be a key challenge for any small molecule HPK1 inhibitor when evaluating the clinical potential. 20 To date, although a number of small-molecule HPK1 inhibitors that exhibit excellent inhibitory activity have been discovered (Figure 1), the poor GLK selectivity profile, metabolic stability, permeability, and PK profile limit the further development as clinical candidates, 17,26−28 and no HPK1 inhibitor has been approved in clinical trials yet. Compound 4 is the only potent HPK1 inhibitor reported to exhibit an over 30-fold selectivity within GLK kinase, and it obtained an oral bioavailability of approximately 100% in a mouse model.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy

Wang

et al. 2022

J. Med. Chem.

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Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies. The biggest challenge of HPK1 inhibitor design is to achieve a higher selectivity to GLK, an HPK1 homology protein as a positive regulator of T-cell activation. Herein, we report the design of a series of macrocycle-based HPK1 inhibitors via a conformational constraint strategy. The identified candidate compound 5i exhibited HPK1 inhibition with an IC 50 value of 0.8 nM and 101.3-fold selectivity against GLK. Compound 5i also displayed good oral bioavailability (F = 27−49%) in mice and beagles and favorable metabolic stability (T 1/2 > 186.4 min) in human liver microsomes. More importantly, compound 5i demonstrated a clear synergistic effect with anti-PD-1 in both MC38 (MSI) and CT26 (MSS) syngeneic tumor mouse models. These results showed that compound 5i has a great potential in immunotherapy.

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“…Loss of HPK1 kinase function in HPK1 kinase-dead (HPK1.kd) knockin mice enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. , A synergistic effect in controlling tumor growth was also observed when anti-PD-L1 was used to treat HPK1.kd mice . These results, coupled with emerging studies of small-molecule HPK1 inhibitors, − suggest that HPK1 could be an excellent drug target for enhancing antitumor immunity. Herein we describe the design and development of novel pyrazolopyridine derivatives as ATP-competitive inhibitors of HPK1.…”

mentioning

confidence: 98%

Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors

Liu

et al. 2022

ACS Med. Chem. Lett.

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In spite of the great success of immune checkpoint inhibitors in immune-oncology therapy, an urgent need still exists to identify alternative approaches to broaden the scope of therapeutic coverage. Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative regulator of activation signals generated by the T cell antigen receptor. Herein we report the discovery of novel pyrazolopyridine derivatives as selective inhibitors of HPK1. The structure–activity relationship campaign led to the discovery of compound 16, which has shown promising enzymatic and cellular potency with encouraging kinome selectivity. The outstanding pharmacokinetic profiles of 16 in rats and monkeys supported further evaluations of its efficacy and safety in preclinical models.

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Inhibitors of immuno-oncology target HPK1 – a patent review (2016 to 2020)

Cited by 22 publications

References 38 publications

HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy in Non-Hodgkin lymphoma

HPK1 inhibitor enhanced tumor response to anti-PD-1 immunotherapy in Non-Hodgkin lymphoma

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy

Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors

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