A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL

Naing, Aung; Leong, Stephen; Pishvaian, Michael J.; Razak, Albiruni Ryan Abdul; Mahipal, Amit; Berlin, J.; Cho, D.; Senapedis, William; Shacham, Sharon; Kauffman, Michael; Ellis, Jennifer; Meade, Julie; Baloglu, Erkan

doi:10.1093/annonc/mdx367.008

Cited by 17 publications

(10 citation statements)

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“…A Phase 1 clinical trial (NCT02702492) evaluated the efficacy of KPT-9274 in patients with advanced solid malignancies or NHL. In agreement with our current findings, evaluable response and NAPRT1 dependent rescue with niacin were observed in patients on this trial [ 44 ]. This has allowed further room for dose escalation, which is currently ongoing.…”

Section: Discussionsupporting

confidence: 93%

PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma

Khan

Uddin

Balasubramanian

et al. 2021

Cancers

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Diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma (FL), and mantle cell lymphoma (MCL) are aggressive non-Hodgkin’s lymphomas (NHL). Cure rates are suboptimal and novel treatment strategies are needed to improve outcomes. Here, we show that p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) is critical for lymphoma subsistence. Dual targeting of PAK4-NAMPT by the Phase I small molecule KPT-9274 suppressed cell proliferation in DLBCL, FL, and MCL. Growth inhibition was concurrent with apoptosis induction alongside activation of pro-apoptotic proteins and reduced pro-survival markers. We observed NAD suppression, ATP reduction, and consequent cellular metabolic collapse in lymphoma cells due to KPT-9274 treatment. KPT-9274 in combination with standard-of-care chemotherapeutics led to superior inhibition of cell proliferation. In vivo, KPT-9274 could markedly suppress the growth of WSU-DLCL2 (DLBCL), Z-138, and JeKo-1 (MCL) sub-cutaneous xenografts, and a remarkable increase in host life span was shown, with a 50% cure of a systemic WSU-FSCCL (FL) model. Residual tumor analysis confirmed a reduction in total and phosphorylated PAK4 and activation of the pro-apoptotic cascade. This study, using various preclinical experimental models, demonstrates the therapeutic potential of targeting PAK4-NAMPT in DLBCL, FL, and MCL. The orally bioavailable, safe, and efficacious PAK4-NAMPT dual inhibitor KPT-9274 warrants further clinical investigation.

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Section: Discussionsupporting

confidence: 93%

PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma

Khan

Uddin

Balasubramanian

et al. 2021

Cancers

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“…In this model there was a robust survival advantage in animals treated with immune checkpoint inhibitor plus NAMPT inhibitor ( 158 ). A phase I study of KPT-9274 was recently completed ( 159 ), and a study of KPT-9274 in combination with nivolumab for melanoma was enrolling patients but recently terminated ( 160 ).…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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“…76 The first-in-human study, dosing patients with solid tumors, alone or in combination with NA, was first reported in 2017. 77 2.6.2. NAMPT Inhibitor Discovery and Development.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death

Velma,

Krider,

Alves

et al. 2024

J. Med. Chem.

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Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD+ biosynthesis via salvage of NAM formed from catabolism of NAD+ by proteins with NADase activity (e.g., PARPs, SIRTs, CD38). Depletion of NAD+ in aging, neurodegeneration, and metabolic disorders is addressed by NAD+ supplementation. Conversely, NAMPT inhibitors have been developed for cancer therapy: many discovered by phenotypic screening for cancer cell death have low nanomolar potency in cellular models. No NAMPT inhibitor is yet FDA-approved. The ability of inhibitors to act as NAMPT substrates may be associated with efficacy and toxicity. Some 3-pyridyl inhibitors become 4-pyridyl activators or “NAD+ boosters”. NAMPT positive allosteric modulators (N-PAMs) and boosters may increase enzyme activity by relieving substrate/product inhibition. Binding to a “rear channel” extending from the NAMPT active site is key for inhibitors, boosters, and N-PAMs. A deeper understanding may fulfill the potential of NAMPT ligands to regulate cellular life and death.

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A first in human phase 1 study of KPT-9274, a first in class dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies or NHL

Cited by 17 publications

References 0 publications

PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma

PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma

Clinical development of metabolic inhibitors for oncology

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death

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