Author: Machado-Neto, João Agostinho ; Lima, Keli ; Velloso, Elvira Deolinda Rodrigues Pereira ; da Silva, Wellington Fernandes ; Cipelli, Marcella ; Leal, Aline de Medeiros ; Schuringa, Jan Jacob ; Câmara, Niels Olsen Saraiva ; Pereira-Martins, Diego Antonio ; Nogueira, Frederico Lisboa ; Carvalho, Maria Fernanda Lopes ; Nardinelli, Luciana ; Bendit, Israel ; Cavaglieri, Rita de Cássia ; Rego, Eduardo Magalhães

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.

01 May 2020·Cell Chemical BiologyQ1 · BIOLOGY

Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Q1 · BIOLOGY

Article

Author: Hao, Ming-Feng ; Yang, T Jonathan ; Zhang, Tinghu ; Seo, Hyuk-Soo ; Gray, Nathanael S ; Browne, Christopher M ; Kwiatkowski, Nicholas P ; Paddock, Marcia N ; Shim, Hyeseok ; Cunningham, James M ; Sivakumaren, Sindhu Carmen ; Jiang, Baishan ; Wang, Diana G ; Manz, Theresa D ; Lundquist, Mark R ; Krishnan, Pranav ; Marto, Jarrod A ; Cantley, Lewis C ; Ficarro, Scott B ; Ferguson, Fleur M ; Dhe-Paganon, Sirano

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

12 Mar 2020·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Structure–Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Q3 · MEDICINE

Article

Author: Shen, Min ; Hall, Matthew D. ; Ficarro, Scott B. ; Sivakumaren, Sindhu C. ; Dhe-Paganon, Sirano ; Simeonov, Anton ; Card, Joseph D. ; Ferguson, Fleur M. ; Boxer, Matthew B. ; Manz, Theresa D. ; Yasgar, Adam ; Marto, Jarrod A. ; Shim, Hyeseok ; Gray, Nathanael S. ; Zhang, Tinghu ; Cantley, Lewis C. ; Seo, Hyuk-Soo ; Sasaki, Atsuo T. ; Davis, Mindy I.

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, compound 30 represents a highly selective pan-PI5P4K covalent lead molecule.

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	Preclinical	BR	University of Sao Paulo	11 Dec 2022
Neoplasms	Preclinical	US	Harvard University	21 May 2020

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