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NAMPT Inhibitors

From EverybodyWiki Bios & Wiki



NAMPT and Cancer

Nicotinamide adenine dinucleotide (NAD) is an electron carrier that plays a crucial role in metabolic pathways such as Tricarboxylic Acid (TCA) cycle, glycolysis and oxidative phosphorylation. The reprogramming of energy metabolism, being one of the hallmarks of cancer, [1] involves cancer cells having a higher adenosine triphosphate (ATP) demand compared to healthy cells. [2] This increase in ATP demand leads to a further increase in NAD(P). Therefore, there are numerous pathways, like Salvage and De novo pathway, that come into play to ensure NAD turnover in cells, cancer cells especially.[3]

De novo pathway involves the generation of NAD from precursors obtained from diet, like tryptophan, nicotinamide, nicotinic acid or nicotinamide riboside.

Salvage pathway, which involves the re-use of nicotinamide liberated by NAD-utilizing enzymes, occurs predominantly to ensure NAD levels remain unchanged. Nicotinamide phosphoribosyltransferase (NAMPT) converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN). Nicotinamide mononucleotide adenylyltransferase (NMNAT) then catalyzes the synthesis of NAD from NMN.[4]

Hasmann et al. reported NAMPT, a crucial rate-limiting enzyme of the Salvage pathway, to be an anti-cancer agent, due to its over expression in various cancers, and the high rate of production and utilization of NAD in cancer cells. The first inhibitor of NAMPT, FK866, also known as APO866 was then first presented in 2003. [5] [6] [7] [8] [9] [10] [11] [12][13] This resulted in clinical trials of various proposed anti-cancer molecules, with no recent progress to later stages.

NAMPT Inhibitors

Clinical Trial Data of NAMPT inhibitors[3]
Drug Phase No. of Patients Treatments Condition or Disease Outcomes Results Dose-limiting toxicities State ID
APO866 I/II 10 IV infusion at 0.126mg/m2/h for 4 consecutive days (1 cycle) B-cell chronic lymphocytic leukaemia Safety and tolerability Stable disease in most patients Thrombocytopenia Completed NCT00435084[14]
APO866 II 25 0.126 mg/m2/h IV every 4 weeks for 4 consecutive days (3 cycles) Melanoma Determine the tumor response rate Stable disease in most patients Thrombocytopenia Completed NCT00432107[15]
APO866 II 25 0.126 mg/m2/h IV every 4 weeks for 4 consecutive days (3 cycles) Cutaneous T-cell lymphoma Safety and tolerability; tumor response Stable disease in most patients Lymphocytopenia; Thrombocytopenia Completed NCT00431912 [16]
CHS-828 (GMX1778) I <50 Range of concentration, 20-500 mg once every 3 weeks PO Solid tumors Pharmacokinetics study Stable disease in most patients or no results posted Thrombosis; vomiting; diarrhea; thrombocytopenia; leucopenia Withdrawn NCT00003979 [17] [18] [19]
GMX1777 I 19 60-200 mg/m2/24 h IV infusion once every 3 weeks Solid tumors and lymphomas Determine the recommended phase II dose No results posted GI hemorrhage; thrombocytopenia; tash Withdrawn (due to financial constraints) NCT00457574 [20]
GMX1777 I/II 1 actual Combination with temozolomide Metastatic melanoma Determine the recommended phase II dose No results posted No results posted Terminated (due to financial constraints) NCT00724841
KPT-9274 (ATG-019) I 175 Oral KPT-9274 three times a week every other day; 500 mg niacin ER co-administered with each dose of oral KPT-9274 three times a week every other day Solid malignancies or non-Hodgkin's lymphoma (NHL) Determine the maximum tolerated dose and dose-limiting toxicities No results posted No results posted Recruiting NCT02702492
KPT-9274 (ATG-019) I 70 Alone: A starting dose of 30 mg with niacin: A starting dose of 60 mg ATG-019 and 500 mg niacin ER Solid tumors or non-Hodgkin's lymphoma (NHL) Determine the maximum tolerated dose and dose-limiting toxicities No results posted No results posted Not yet recruiting NCT04281420
OT-82 I 50 The starting OT-82 dose level will be 16.5 mg/m2 give orally as an oral suspension once Relapsed or refractory lymphoma Determine the dose-limiting toxicities or response rate No results posted No results posted Recruiting NCT03921879

Toxicity of NAMPT inhibitors

Clinical trials with NAMPT inhibitors revealed dose-limiting toxicity. The most prominent dose-limiting toxicity in patients receiving treatment in solid tumor phase I and phase II clinical studies. These findings were replicated in in vivo pre-clinical models and indicate that other bone marrow-related toxicities, such as anaemia and neutropenia, are also expected . Thrombocytopenia is on-target but only occurs at high dosages. [21]

Although it was not mentioned in the clinical trials, retinal and heart toxicity have also been proposed in preclinical investigations to be dose-limiting adverse effects in addition to haematological toxicities. [22] Although these have been labelled as on-target side effects, a recent study from our team revealed that not all NAMPT inhibitors carry these hazards because we discovered NAMPT inhibitors that did not cause retinal or cardiotoxicity. [23]This problem needs more research and could be caused by the chemicals' physiochemical characteristics, such as their lipophilicity. Last but not least, in animal models, it has also been hypothesised that NAMPT inhibitors may cause hepatic steatosis. [24]

Therefore, the totality of the data suggests as a conclusion NAMPT inhibitors as single agents likely have substantial toxicity, comparable to that of conventional chemotherapeutic medicines, and consequently, strategies that lessen this should be sought, including the potential to increase NAPRT activity in healthy cells.

Mechanisms of actions of NAMPT inhibitors

Sirtuin Function

Sirtuins are a group of NAD-dependent histone deacetylases and ADP-ribosyltransferases that are involved in many processes like proliferation, apoptosis, cell metabolism, caloric restriction, and cell survival. [25] There are numerous studies that describe the role of NAD-consuming sirtuins in cancer and benefits of targeting these molecules for anti-cancer therapy.[26]

An understanding of NAMPT's function in sirtuin expression is one of these findings. [27] Several groups have reported using CRC models to NAMPT is a mediator in the regulation of SIRT1 activity. In a few instances, it was shown that NAMPT was a direct transcriptional target of c-Myc, leading to a positive feedback loop involving c-Myc, NAMPT, and SIRT1 that fueled the proliferation and development of tumour cells. These investigations shown that the use of NAMPT inhibitors reduced tumour cell proliferation in CRC models by decreasing SIRT1 expression and TP53 derepression. [28] [29] [30] [31] Gastric cancer models [32] and prostate cancer models [33] have both shown the same effect.

Experimental induction of NAMPT has been shown to have a corresponding effect on SIRT1 activity in cancers where a direct regulatory link between NAMPT and the sirtuins has not yet been clarified [34], whereas genetic or pharmacological inhibition of NAMPT has resulted in decreased SIRT1, [35] [36] [37] [38]SIRT2,[39] and SIRT3. [40] Since changes in SIRT1 expression with NAMPT inhibition have not been seen in all NAMPT inhibitor-sensitive cells, it is interesting to note that the functional impact of NAMPT on sirtuins is likely cancer cell type specific. [41] These variations might be crucial for the practical application of NAMPT inhibitors because they might influence which cancer types are more responsive to NAMPT inhibitors. [42][43]

DNA Damage Repair Response

The poly-ADP ribose polymerases (PARPs) are a different class of NAD+-dependent proteins that consume a sizable amount of cellular NAD+.[44] In addition to other things, PARPs play a crucial role in the recognition and repair of DNA damage.[45] Therefore, a lack of NAD+ is projected to lead to a reduction in DNA damage repair. On the basis of decreased PARP activity with NAMPT inhibitor use in numerous cancer models, preclinical testing of NAMPT inhibitors coupled PARP inhibitors in Ewing sarcoma and triple-negative breast cancer was done.[46] [47] Both studies observed synergy between NAMPT and PARP inhibitors. In the breast cancer study, the effect was seen to be highest in BRCA-deficient mice, suggesting that underlying homologous recombination (HR) deficits may further improve the efficiency of NAMPT inhibition.

Data showing that NAMPT inhibition impairs non-homologous end joining and increases cellular reliance on HR [48] confirm this. BRCA1 and NAMPT have been shown to regulate one another in ovarian cancer models.[49] Ewing sarcoma, which is not BRCA-deficient, is similarly characterized by poor HR,[50] supporting the hypothesis that tumours with flawed DNA repair pathways may be more vulnerable to NAMPT inhibition. NAMPT and PARP inhibitors were found to be functionally antagonistic in a recent work using preclinical leukaemia models, which raises the possibility that these pathways interact differently depending on the cell type. [51]

It has been determined that NAMPT inhibitors are selectively sensitive to other cancer types with deficiencies in DNA repair. Excision repair cross complementation group 1 (ERCC1)-deficient non-small cell lung tumors (NSCLC) were incredibly sensitive to NAMPT inhibitors, both in vitro and in vivo.[52] Since mitochondrial defects are also related to ERCC1 deficiency, it is possible that other factors affect how sensitive this cancer subtype is to NAMPT inhibitors. NAPRT expression, a crucial enzyme in the Preiss-Handler pathway, was associated with a BRCA gene expression  characteristic to ovarian cancer, and cells with this signature were more vulnerable to NAMPT inhibitors. Numerous effects, including decreased PARylation, [53] decreased RAD51, and impaired double-strand break repair by the HR pathway, have been described in mechanistic studies of the downstream effects of NAMPT inhibitors on DNA damage repair.[54]

These observations prompted other research to investigate the effectiveness of NAMPT inhibitors in the presence of DNA-damaging substances. Radiation, [55] DNA alkylating agents, [56] [57]topoisomerase inhibitors, or other classes of chemotherapy known to amplify the effects of impaired DNA repair [58] [59] [60]have all been reported to have enhanced antitumor activity when combined with genetically or pharmaceutically inhibiting NAMPT. Surprisingly, an increase in efficacy in some cancers was limited to combinations with only specific chemotherapeutic agents, as in preclinical studies in pancreatic cancer models where it was discovered that gemcitabine, but not 5-fluorouracil (5-FU) or oxaliplatin, enhanced the anti proliferative effect of NAMPT inhibitors. [61] NAMPT inhibitors' synergistic effects with medications from various chemotherapeutic classes were comparable in other investigations. The underlying causes of these variations remain unknown. Last but not least, a study characterizing the effects of resistance to NAMPT inhibitors in CRC cell lines revealed changes in the expression of genes involved in DNA repair and an increased sensitivity to DNA damaging agents, further pointing to an intimate relationship between NAMPT dependence and DNA damage repair. [62] When considered collectively, these findings have clinical ramifications because they imply that tumors with specific defects in DNA repair mechanisms may be selectively sensitive to NAMPT inhibitors and that chemotherapies may be used in combination with this class of drugs to increase their efficacy, particularly in certain tumor types.

Redox homeostasis

Cellular ROS levels are significantly regulated by NAD+, which can accumulate when levels are low. This is particularly true for cancer cells, which necessitate strict control over the equilibrium of ROS. Inhibition of NAMPT disturbs the equilibrium of ROS.[63] [64] [65]

It has been demonstrated that NAMPT helps cells endure oxidative stress. It raises the levels of NADH and NAD+ that can be converted to NADPH via the pentose phosphate pathway, as well as protecting cells against oxidative stress. Through a decrease in anti oxidative activity, NAMPT inhibition also increases the vulnerability of cancer cells to oxidative stress.[66] [67]

In models of NSCLC, leukaemia, prostate cancer, breast cancer, glioblastoma, CRC, and other malignancies, it has been demonstrated that NAMPT depletion or inhibition increases ROS. It is important to note that all cancers do not show an increase in ROS after NAMPT inhibition, indicating that these effects may vary depending on the kind of cancer cell. This might be because specific tumours have active compensatory NAD+ synthesis pathways, like the Preiss-Handler route.[68]

NAMPT inhibitors have been demonstrated to be more effective against pancreatic adenocarcinoma cells and NSCLC models when combined with ROS generating drugs, according to studies. Additionally, the formation of intracellular reduced glutathione, ROS, and breast cancer cell death were all influenced by the addition of a NAMPT inhibitor to a plasma-activated media that included ROS.[69] [70]

Oncogenic Signaling

In numerous cancer models, NAMPT and oncogenic signalling pathways have been shown to interact, making co-targeting of NAMPT and these pathways advantageous. While NAMPT sometimes controls the expression of oncogenic factors, other times it controls the functioning of oncogenic signalling pathways. It has been discovered that exogenous eNAMPT causes the phosphorylation of AKT and ERK1/2 and boosts breast cancer cell growth. NAMPT inhibitors and ERK1/2 inhibition together increased cell death. [71][72] [73]

A number of cancers, including hepatocellular carcinoma, leukaemia, pancreatic ductal adenocarcinoma, and pancreatic neuroendocrine tumour cells, have been linked to NAMPT suppression and lack of activation of mTOR and its downstream targets. NAMPT inhibition was linked to mTOR activation loss in myeloma mice, which was assumed to be a factor in autophagic death. Non-cancerous cells treated with NAMPT inhibitors did not experience changes in AMPKa or mTOR.[74]

Studies have demonstrated that the addition of NAMPT inhibitors can overcome the resistance of melanoma cells to BRAF inhibitors, and that inducing the expression of NAMPT can do the same for normal cells.[75]

Since EGFR, HER2, and oestrogen receptor positivity are all correlated with NAMPT expression, co-targeting NAMPT with other signalling pathway molecules may be a promising treatment approach. [76]

Epithelial-Mesenchymal Transition and Stemness

One known modulator of cancer cell stemness is NAMPT. Studies on clinical CRC tumour samples demonstrated a correlation between high NAMPT expression and a large percentage of cancer-initiating cells. High NAMPT expression was seen in glioblastoma tumours and patient-derived stem-like cells. Glioblastoma stem cells were less able to self-renew and create in vivo tumours when NAMPT was pharmacologically and genetically inhibited. Additionally, NAMPT suppression prevented cancer cells from dedifferentiating.[77] [78]

Epithelial-mesenchymal transition (EMT) in cancer cells is impacted by NAMPT inhibition. Pharmacological NAMPT inhibition altered EMT marker proteins and decreased the ability of hepatocellular carcinoma cells to invade and produce metastases. NAMPT overexpression and exogenous eNAMPT triggered EMT and aided osteosarcoma cell motility and invasion in breast cancer cell lines. NAMPT suppression reduced glioma cell motility. [79] NAMPT inhibition boosted cellular invasiveness and activated EMT in lung cancer cell lines. NAMPT inhibition promoted metastatic behaviour in breast cancer model organisms.[80] It is crucial to comprehend how NAMPT inhibition affects metastasis because this effect can vary depending on the type of cancer. [81]

Immune Regulation of Tumor Microenvironment

The expression of CXCR4 in hematopoietic cells has been found to be negatively regulated by NAMPT, which causes immature myeloid-derived suppressor cells (MDSCs) to become active. The immunosuppression was reversed and the tumor cells were once again sensitive to immunotherapeutic treatments as a result of pharmacologic inhibition of NAMPT. [82]

In murine cancer models as well as in people with melanoma and head and neck cancer, NAMPT has been found to be increased in tumor associated neutrophils (TANs). Ex vivo TANs that have NAMPT inhibition reduced tumor angiogenesis and proliferation after being adopted into tumor-bearing mice. To fully comprehend the function NAMPT inhibition plays in the immunological microenvironment, more research is required.[83]

Dual Inhibitors

NAMPT inhibitors are capable of being paired with other medications to lessen the capacity of cancer cells for defence and metabolism. Apoptosis and DNA damage have been proven to increase with this combination. The idea of combining NAMPT inhibitors with drugs that have various modes of action has been investigated by a number of scientists.[84]

Drug combinations have been pursued to overcome pharmacokinetic problems associated with simultaneous use of two drugs. The structure of all NAMPT inhibitors allows for hybrid molecules with two well-balanced mechanisms of action. In fact, while the pyridine ring is typically crucial as the cap group to produce strong compounds, the chemical makeup of the so-called tail group, which extends beyond the enzyme, is less essential as illustrated above and is thus accessible to recognition of alternative targets.[85]

Two prime instances of this innovative class of chemicals are STF-31 and KPT-9274. KPT-9274 inhibits both p21-activated kinase (PAK4) and NAMPT with significant cytotoxic effect on B-ALL cells and the capacity to work in vivo in a xenograft mouse model. It is the foremost NAMPT inhibitor of the forthcoming second phase to undergo clinical trials, however no results have been reported as of yet. [86] [87]

Epacadostat and pyridine derivatives, hybrid molecules with inhibitory activity against NAMPT and IDO-1 or HDAC, have been developed. Stronger tumor-suppressing, T cell proliferation, and anti-tumor efficacy have all been demonstrated by these hybrids. Pure NAMPT inhibitors have also been demonstrated to indirectly reduce MDSC activity, which in turn inhibits T cell growth, in living organisms.[88] [89]

Finally, using a pharmacophore fusion strategy, the same research team has revealed two distinct NAMPT-HDAC hybrid inhibitors. The cause of this fusion was the discovery that NAMPT inhibitors, such as FK866, could increase the inhibitory impact of HDACs acting synergistically in the anticancer effect.[90] [91]

Future Prospects

NAMPT is a desirable therapeutic target in the treatment of cancer because of the crucial part NAD+ plays in the growth and survival of malignant cells. NAMPT is implicated in sirtuin function, support of DNA repair processes, maintenance of redox balance, molecular signaling, determination of cellular states, and tumor-related immune suppression in addition to its role in cellular energy metabolism. NAMPT inhibitors may be able to suppress several of these other processes, depending on the type of cancer cell. Additionally, combination therapies with drugs that complementarily target these functions have the potential to significantly boost the effectiveness of NAMPT inhibitors. The use of NAMPT inhibitors in combination with other drugs in the preclinical context has been described in an increasing number of papers as having additive or synergistic effects. Clinical application of these logical combinations is the next step given that phase 1 evaluation of newer generation NAMPT inhibitors is currently underway.[92]

Careful patient selection gives an additional chance to maximize the efficacy of these drugs, in addition to creating logical combination regimens with NAMPT inhibitors. For instance, tumors with NAPRT deficiency [93] [94]and malignancies with IDH mutations [95] [96] have both been demonstrated to display remarkable sensitivity to NAMPT inhibitors. Recognition of specific weaknesses in the non-metabolic pathways promoted by NAMPT, such as HR deficit or EMT targeting for metastatic illness, may also serve as a guide for choosing patients. The potential to use antibodies or minuscule chemical entities to specifically target NAMPT in its extracellular form is a fascinating last remark. NAPRT, which is currently emerging as a potential novel target but for which no particular inhibitors are at this time available, should be taken into account as the final factor.

It is possible to identify additional biological components. For instance, if NAMPT is essential for nuclear NAD, then PARP inhibitors may make effective therapeutic partners.[97] [98] This is merely an example of how programmes in medicinal chemistry can function much more effectively if one understands the biology of the protein. While it is still unknown whether the immunotherapeutic effect is obtained at similar levels in humans or if dose adjustments are required, the use of the medicine in combination might perhaps also reduce toxicity. Therefore,  considering the option of dual inhibitors, would take this research in the right direction. 

In conclusion, it is crucial to comprehend how NAMPT and NAMPT inhibitors affect both the energetic and non-energetic cellular functions of NAD+ in cancer since these knowledge may be crucial for the development of this class of drugs in the future.

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