Anti-Cancer Agents in Medicinal Chemistry (v.13, #9)

Geriatric Evaluation of Oncological Elderly Patients by Michele Malaguarnera, Paola Mariangela Frazzetto, Ozyalcn Erdogan, Alessandro Cappellani, Emanuela Cataudella, Massimiliano Berretta (1300-1309).
Cancer has a high prevalence in older age. The management of cancer in the older aged person is an increasingly common problem. Age may be construed as a progressive loss of stress tolerance, due to decline in functional reserve of multiple organ systems, high prevalence of comorbid conditions, limited socioeconomic support, reduced cognition, and higher prevalence of depression. In the elderly, the comorbidities and physiological changes in the pharmacokinetics reduce the prospective for therapy and suggest the importance of a multidimensional assessment of cancer patients as well as the formulation of predictive models of risk, in order to estimate the life expectancy and tolerance to treatment. The pharmacological changes of age include decreased renal excretion of drugs and increased susceptibility to myelosuppression, mucositis, cardio toxicity and neurotoxicity. The chemotherapy in patients older than 75 years is very limited. The geriatric assessment is considered a valid tool in geriatric medical. It is important for two main reasons: first of all, for the need to distinguish the features linked to the geriatric syndromes from those ones which are strictly connected to the cancer pathology; secondly, for its potential prognostic value.

Cancer, Aging and Immune Reconstitution by Stefania Zanussi, Diego Serraino, Riccardo Dolcetti, Massimiliano Berretta, Paolo De Paoli (1310-1324).
Aging is a complex phenomenon involving multiple physiological functions. Among these, very important are the modifications induced in the immune system; these modifications may be related to cancer development, a disease of older people. We herein describe the age-dependent alterations observed in the various arms of the immune system. Both innate and adaptive immunity are compromised during aging, a condition where an inflammatory status contributes to promote immune suppression and tumour growth. Collectively, aging of the immune system may produce detrimental consequences on the response against tumours in old patients. In fact, preclinical studies and clinical observations in humans have demonstrated age-associated alterations in antitumor immunity. Immunological recovery of old patients after conventional chemotherapy (CT) has not been fully investigated, while several studies conducted in patients undergoing blood stem cell transplantation have demonstrated that a delayed immune reconstitution associated with older age results in increased susceptibility to opportunistic infections and risk of tumour relapse. Cellular immunotherapy and vaccination are becoming viable options for improving survival and quality of life of cancer patients targeting both the host defences and the tumour. The clinical experience in elderly patients is still in its infancy, but available data indicate that these approaches are feasible and promising. A key problem in the studies on aging, immunity and cancer is that it is difficult to distinguish changes related to age from those related to cancer-dependent immunosuppression, but independent from the age of the subject. Longitudinal studies on aged healthy and cancer persons and the use of new immunological techniques may be required to clarify these issues.

Medical Treatment Of Elderly Patients With Breast Cancer by Sergio Palmeri, Massimiliano Berretta, Laura Palmeri (1325-1331).
We performed a bibliographic electronic search of MEDLINE and Cochrane databases on breast cancer in the elderly. In the adjuvant setting aromatase inhibitors are more effective than tamoxifen with an acceptable profile of toxicity. In aged, poorer risk, patients adjuvant chemotherapy is feasible but organ function and comorbidities have to be considered. Adjuvant trastuzumab is also an option for the treatment of Her2 positive aged breast cancer. Neoadjuvant chemotherapy ± HER2-targeted treatment is today a possible treatment for triple negative and HER2-positive disease, respectively. Older women are more likely than younger women to present with more advanced breast cancer. Hormone therapy is the treatment of choice for older women with hormone receptor positive metastatic breast cancer until they develop resistance. When appropriate, polychemotherapy may be employed but unfortunately we have a lack of data on this matter. However, because fit women older than 70 years of age have similar results with chemotherapy as their younger counterparts most oncologists tend to propose this option to their patients. Trastuzumab has proven to be effective and well tolerated in elderly patients (older than 60-70 years), but caution is needed due to the risk of heart failure. Recently, an all-oral combination of capecitabine and vinorelbine demonstrated good acitivity and tolerability profile in patients older than 70 years. Nab-paclitaxel has shown a safer and more active profile compared with the q3w taxanes in such population. There is, therefore, an urgent need to study anticancer agents in the elderly within large randomized controlled trials.

Colorectal Cancer in Elderly Patients: From Best Supportive Care to Cure by Massimiliano Berretta, Fabrizio Di Benedetto, Raffaele Di Francia, Emanuele Lo Menzo, Sergio Palmeri, Umberto Tirelli, Paolo De Paoli (1332-1343).
Colorectal cancer is one of the major causes of cancer mortality in the elderly population (median age at diagnosis of 71 years) in Western Countries. Moreover patients with metastatic disease are often elderly with significant co- morbidities. Unfortunately, elderly patients are often untreated and under-represented in clinical trials, even if most clinical trials that have included this setting of population have shown similar survival rates and toxicities to younger patients.;Age itself should not be considered for candidacy to chemotherapy but it should be taken in consideration the great heterogeneity of co-morbidities present in the elderly population. Therefore, the best treatment strategy for elderly colorectal cancer patients has not yet been defined. Comprehensive Geriatric Assessment is recommended to evaluate the best strategy treatment and to reduce the adverse events. In fact, while fit elderly patients could receive the same therapeutic treatment as the younger counterpart, a palliative approach should be taken in consideration for frail elderly patients and for those with a short life expectancy.

Oxaliplapin and Capecitabine (XELOX) Based Chemotherapy in the Treatment of Metastatic Colorectal Cancer: The Right Choice in Elderly Patients by Massimiliano Berretta, Giuseppe Aprile, Guglielmo Nasti, Martina Urbani, Alessandra Bearz, Stefania Lutrino, Luisa Foltran, Laura Ferrari, Renato Talamini, Francesco Fiorica, Arben Lleshi, Vincenzo Canzonieri, Chiara Lestuzzi, Eugenio Borsatti, Rossella Fisichella, Umberto Tirelli (1344-1353).
Purpose: Elderly patients with metastatic colorectal cancer (mCRC) differ from the general population and are underrepresented in clinical trials. We, retrospectively, analyzed the safety and efficacy of XELOX regimen in the treatment of elderly patients affected by mCRC.;Patients and methods: One-hundred-eleven consecutive patients, aged 70 years or older, were enrolled in the study.;Results: All patients were evaluated for safety and efficacy (male/female, 63/48). Median age was 75 years (range 71-85 years). Median Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0 (range 0-2). Metastatic sites distribution is as follows: liver (44.1%), lung (13.5%), liver plus lung (12.6%) and other (29.7%). A total of 584 cycles were administered (median 6 cycles/patient, range 2-10). Median follow-up time was 14.5 months (range 1-41 months). In an intent-to-treat analysis, objective responses and stable disease were recorded in 41 (40.4%) and 29 (26.6%) patients, respectively. The median response duration was 5.9 months (range 0.5-28.8). The median progression free-survival (PFS) was 7.5 months (range 1-26 months). The median overall survival (OS) was 15 months (range 1-64 months). The grade 3 toxicities were: neutropenia (8.1%), diarrhea and neurotoxicity (5.4% respectively). Most adverse events were mild to moderate; the most common was acute sensory neuropathy (57.6%).;Conclusion: XELOX is a highly effective first-line treatment for mCRC elderly patients. Response rates, PFS and OS are similar to those observed with fluorouracil/leucovorin/oxaliplatin combinations. XELOX is a convenient regimen, likely to be preferred by both patient and healthcare providers.

Onco-Surgical Management of Colo-Rectal Liver Metastases in Older Patients: A New Frontier in the 3rd Millennium by Fabrizio Di Benedetto, Giuseppe D'Amico, Mario Spaggiari, Umberto Tirelli, Massimiliano Berretta (1354-1363).
Colorectal cancer (CRC) is one the most common malignant tumors in industrialized countries today. Over half of all cancers are currently diagnosed in elderly patients, and 76% of all colorectal cancer patients are diagnosed between 65 and 85 years old. Elderly patients are less likely to undergo curative surgery, and less likely to be offered the option of metastasectomy when colorectal liver metastases (CLM) are present. Hepatic resection has become the standard care for the treatment of isolated CLM. However, in studies reporting resection of CLM only 8-20% of the patients are older than 70 years. When balancing the benefits of surgical resection of liver metastases against the potential risks of surgery, many clinicians are still reluctant to advise in favor of surgical treatment in the elderly. Factors other than age should also be considered when evaluating surgical risk in the elderly, for example, conditions such as heart disease and diabetes have been shown to induce life-threatening postoperative complications. Age alone need not be a contraindication to aggressive surgical therapy in this group, rather, appropriate selection criteria based on tumor characteristics and general medical fitness, similar to those used for younger patients, should be applied.

Gastrointestinal Non Colorectal Cancer. Do Elderly Patients Need a Specific Management? by Lucrezia Silvestro, Guglielmo Nasti, Alessandro Ottaiano, Massimo Montano, Rossana Casaretti, Antonio Avallone, Massimiliano Berretta, Carmela Romano, Antonio Cassata, Salvatore Tafuto, Rosario Vincenzo Iaffaioli (1364-1370).
Background: Elderly patients (65 years and over) develop often, sometimes predominantly , esophageal, gastro esophageal junction, gastric and pancreatic cancer (gastrointestinal non colorectal cancer). Most clinical trials exclude elderly patients from accrual considering aging a potential risk factor. In fact an elderly patient can develop greater toxicity than a younger patient from oncologic treatments (chemotherapy, radiotherapy, target therapies) due to a worse function of vital organs.;Methods: We analyzed the current scientific literature, searching articles since 1990, about gastrointestinal non colorectal cancer in elderly patients, to establish if they need a specific management, different from younger patients.;Results: Data from analyzed studies, both gastro esophageal and pancreatic cancer, are contradictory. In some reports elderly patients don't seem to bring greater toxicity than younger. Other trials consider that dose-adjustment to renal function is need in elderly patients, but these trials are very few. Other trials may include several biases such as accrual of “only fit” elderly patients.;Conclusions: It is very important in elderly patients with higher risk of toxicity, to distinguish the aim of cancer treatment: is it curative or palliative? Furthermore, in this type of patients the most important target is probably maintaining the quality of life especially in gastric and pancreatic cancer that often started as advanced disease. For these valuation chronological age alone is not sufficient. Another very important factor in elderly cancer patients is the geriatric assessment including not only age but also functional, social and mental status.

Hepatocellular Carcinoma: Beyond the Boundaries of Age by Fabrizio Di Benedetto, Giuseppe Tarantino, Cristiano Quintini, Umberto Tirelli, Massimiliano Berretta (1371-1377).
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, and the management of HCC has radically changed in recent years. Over the last few years, many elderly patients have been considered less amenable to effective treatments compared to younger patients, due to the accumulation of different diseases during their lives. This assumption has now been reviewed and some key points have been outlined such as the necessity of a careful selection of patients, which may lead to satisfactory results after the treatment of elderly patients with HCC. The purpose of this study was to make a comprehensive analysis of results from the literature concerning the multimodal treatment of HCC in elderly patients, analyzing the therapeutic options such as liver resection, ablative treatments, liver transplantation and targeted chemotherapy.

Treatment of Elderly Patients Affected by Lung Cancer: Why to Treat, when to Treat and what we Know by Alessandra Bearz, Massimiliano Berretta, Arben Lleshi, Eleonora Berto, Umberto Tirelli (1378-1382).
In the recent years many advances have been achieved in the field of the treatment of lung cancer; with the development of novel therapeutic pathways due to the knowledge of oncologic drivers involved in the carcinogenesis of the lung, as well as the involvement of new radiotherapic and surgical techniques. Nevertheless, the standard treatment for elderly is still debated, mainly because of an underrepresentation of elderly patients in clinical trials. Herein we try to summarize the main guidelines for the treatment of lung cancer, with particular attention for the elderly patients, what we know and what has changed.

Treatment Approaches in Elderly Patients with Head and Neck Cancer by Francesco Perri, Franco Ionna, Ettore Pavone, Francesco Longo, Francesco Caponigro (1383-1390).
Integration of geriatric assessment into cancer clinical practice is strongly needed in squamous cell carcinoma of the head and neck (SCCHN) due to the frequent discrepancy between chronologic and biologic age. Comprehensive Geriatric Assessment (CGA) is a multidimensional assessment tool that examines age-related domains. These parameters can be well assessed by easier tests such as Activity Daily Living and Instrumental Activity Daily Living for functional status; Charlson Comorbidity Index for comorbidity; Mini Mental State examination for cognitive status; Mini Nutritional Assessment for nutritional status; Beers criteria for concomitant drug assumption.;Early stage SCCHN is usually treated with either surgery or radiation therapy. Age is not an exclusion criteria for both modalities, but elderly patients have a higher complication rate. Patients with locally advanced SCCHN are preferably treated with concomitant cisplatin-radiotherapy, but the impact of chemotherapy on survival is lower with increasing patient age. The combination of cetuximab and radiation therapy can be a suitable option in elderly patients with locally advanced SCCHN. However, also in this group of patients, survival benefit is lower in elderly patients. Chemotherapy represents the mainstay of treatment in recurrent/metastatic SCCHN. However, elderly patients can receive more toxicity. Myelosuppression, diarrhea, mucositis, nephrotoxicity and neurotoxicity have to be early diagnosed and adequately treated.;The initial approach for screening elderly SCCHN patients may benefit from relatively easy tests such as Vulnerable Elders Survey 13 (VES-13), which can screen patients who are to undergo full CGA.

Genito-Urological Cancers in Elderly Patients by Giuseppe Morgia, Giorgio Ivan Russo, Massimiliano Berretta, Salvatore Privitera, Ziya Kirkali (1391-1405).
Age is now widely accepted as the greatest single risk factor for developing cancer, and cancer is considered primarily as a disease of the elderly. Furthermore, a characteristic of aging is the progressive deterioration of immune function known as immunosenescence. In addition to the increased risk of occurrence of cancer among older patients, they are more predisposed to poor outcomes after definitive treatment. Therapies, outcomes and mortality are often influenced by age and elderly must have a specific and a multidisciplinary approach. It is obvious to consider that one should not consider “age” as the only risk factor, but the condition that this determines to the organism, like the presence of co-morbidities and the consequent poor response to treatment. Cancer occurs frequently in association of one or more other chronic diseases, that affect the efficacy of various treatment interventions. ;Because of the potential morbidity associated with surgery, the use of mini-invasive techniques have expanded considerably. Aging should not be viewed as a difficulty to definitive therapeutic option. For these reason, it should be correct to value the physiologic capabilities of each organ system and all co-morbidities in the elderly, in order to face possible risks of treatment or improbable benefits.; This review takes a look to the tumor biology and to the morbidity of cancer treatment in elderly patients affected by genito-urological cancer like prostate, bladder and renal cancer.

Skin Cancers in Elderly Patients by Giulia Malaguarnera, Maria Giordano, Alessandro Cappellani, Massimiliano Berretta, Michele Malaguarnera, Rosario Emanuele Perrotta (1406-1411).
Cancer in older people is a common problem worldwide. Among various types of cancer, skin cancers represent an important percentage. The principal risk factors are sun exposure, family history of skin cancer, fair skin color, but also the age plays an important role in the genesis of skin cancers. In older people there are a more prolonged exposure to carcinogenesis and a decreased functionality of reparation mechanisms of the cells so they acquire a selective advantage of growing and proliferating. At the same time age causes alteration in immune system by increasing NK-cells absolute number and decreasing both the endogenous and the lymphokine-induced lytic activities.;The anti-tumor immune response is also mediated by the cytotoxic T- lymphocytes and in the elderly a strong reduction of T-cell function has been demonstrated. In elderly patients the diagnosis and the treatment of skin cancers can be different from younger counterpart. For example in older patients with melanoma is important to evaluate Breslow depth while higher mitotic rate has major value in younger patients. Moreover, the treatment should consider the performance status of patients and their compliance.

Management Of Elderly Patients With Diffuse Large B-Cell Lymphomas by Rosanna Ciancia, Umberto Tirelli, Josep-Maria Ribera, Michele Spina (1412-1418).
Life expectancy has impressively increased over the past century and the US population over 65 years is rapidly growing, especially those over 80 years. In fact, persons older than 80 years have increased by more than 250% between the years 1960 and 2000, and it is expected that the population aged >;75 years will triple by the year 2030. With the increase of the geriatric population, there is a need for the development and validation of treatment strategies for NHL for these patients. Therapy in elderly patients needs special attention because older patients usually suffered of several co-morbidities and their management represents a challenge for physicians. In fact, older patients treated for lymphoma may not tolerate the high-dose therapies used in younger patients and have increased risk of therapy-related toxicity as a result of age-related physiological changes and frequent co-morbidities. The widespread use of a comprehensive geriatric assessment tool might overcome the difficulty to run prospective clinical trial in elderly patients with lymphoma.

Autologus Stem Cell Transplatation as a Care Option in Elderly Patients. A Review by Lucia Fratino, Maurizio Rupolo, Mario Mazzuccato, Massimiliano Berretta, Arben Lleshi, Umberto Tirelli, Mariagrazia Michieli (1419-1429).
The ageing population and the increase in life expectancy have put new social and health questions into the public health agenda of western countries. Hematological cancer incidence peaks in older population as a logical consequence of a longer lifespan promoting prolonged exposure to carcinogens and accumulation of genetic alterations. Hematological cancer represents a major cause of mortality in this age group despite recent progress observed in the management of cancer in the general population. Autologous stem cell transplantation (ASCT) represents a therapeutic option in the treatment of a large proportion of lymphomas and multiple myeloma, but their role in the onco-geriatric setting remains an open question, due to the presence of chronic disease. Ageing is characterized by progressive decrements in physiologic reserves and abilities to compensate for physical and/or functional limitations, which increase the risk of developing morbidity and disability. These events explains the extreme diversity of ageing individuals in terms of clinical and functional status. As a consequence, life expectancy in the elderly is influenced not only by the neoplastic diseases itself but also by the various co-morbidities common to this age group. The management of elderly people with hematological diseases potentially curative, should therefore combine both geriatric and tumor assessments. Among the elderly patients identified as being candidates for AHSCT, after the mobilization of progenitor cells from the bone marrow into the peripheral blood, the aphaeresis procedure is the most common method for collecting an adequate number of stem cells. The proper selection of patients may greatly improve the results and the toxicity related to cancer treatment in the elderly. We recommend the adoption of some form of geriatric assessment in the evaluation of any patient who is 70 years and older, this review intends to offer an overview of the state of art in ASCT in elderly patients.

Is Effective and Safe a Radiochemotherapy Approach in Elderly Cancer Patients? A Review by Francesco Fiorica, Antonio Zanghì, Giuliana Pascale, Otilia Nuta, Lino Del Pup, Antonio Stefanelli, Francesco Cartei (1430-1437).
Although more than 60% of all cancer patients in Europe and the USA are older than 65 years at the time of diagnosis, elderly patients are generally under-represented in clinical trials. A general consensus on how to treat elderly patients is still far from being achieved. ;In this review, we address some of the issues and challenges surrounding the treatment of older cancer patients and radiochemotherapy. We discuss the existing evidence related to radiochemotherapy in the elderly, focusing primarily on the malignancies most commonly seen in older patients and making general treatment recommendations where applicable.

Hematopoietic Growth Factors Support in the Elderly Cancer Patients Treated with Antiblastic Chemotherapy by Maurizio Rupolo, Arben Lleshi, Bruno Cacopardo, Mariagrazia Michieli, Massimiliano Berretta (1438-1443).
The 60% of tumors affected patients >;65years of age and the future previsions are considering an amount of 70% after 2030. Elderly Patients presents multiple comorbidity, polipharmacy, and disability. Geriatric assessment helps physicians to take the best therapeutic decisions. Clinical conditions influence efficacy and tolerability of chemotherapy. Prophylactic use of G-CSF after chemotherapy lowers the rate and length of severe neutropenia , and decreases the episodes of febrile neutropenia. Anemia is a hematologic condition associated with ageing , but is frequently associated to concomitant chronic disease. Stem cells display increasing resistance to erythropoietin in the elderly patients and this is connected with the onset of pro-inflammatory cytokines characteristic of this age . Anemia is a common adverse event in cancer patients receiving chemotherapy. Several of the symptoms associated with anemia, such as fatigue, syncope, palpitations and dyspnea, reduce patient activity and have a profound effect on the quality of life [QOL]. Considering the unfit or frail status of elderly patient the at home use of pegfilgrastim and weekly or three weekly erythropoietin administration could be preferred for this setting of patients that lack of specialized nursing care or facilities. Further studies, considering the several differences in health organizations in vary countries, could be held to state the real impact of the biosimilars in comparison to the long acting originators in the reduction of costs in this group of patients.

The Complexity of Aging: Cancer Risk Among Elderly People and Infectious Risk Among Those with Cancer by Marilia Rita Pinzone, Massimiliano Berretta, Hans Wilhelm Doerr, Giuseppe Nunnari, Bruno Cacopardo (1444-1448).
Aging is associated with a reduced capability of the immune system to adequately respond to pathogens and to prevent tumor formation. As a consequence of immunosenescence, older people have a higher risk to develop infections as well as cancer. In addition, cancer itself may expose old patients to infections, including opportunistic infections, i.e. Pseudomonas aeruginosa, Aspergillus fumigatus and Cytomegalovirus infection. Patients with hematologic malignancies have a higher risk than patients with solid tumors, because of more prolonged disease-related and treatment-related neutropenia and intensive immunosuppressive regimens. Co-existing medical conditions, e.g. chronic renal failure, diabetes mellitus, emphysema, which are quite common in the elderly, may also contribute to rising the infectious risk, as well as the use of long term vascular catheters, which is required in a large number of cancer patients to administrate chemotherapy. Neutropenic infections do not only represent a major cause of morbidity and mortality, but may be responsible for a reduction of the antineoplastic treatment dose and dose intensity, thus compromising the overall treatment effectiveness. The use of antibiotic prophylaxis to reduce neutropenia-related infectious complications in patients with cancer is still object to debate. Quinolones represent the most attractive option, since these drugs have a broad antimicrobial spectrum, systemic bactericidal activity, good tolerability and lack of myelosuppression. However, fluoroquinolone prophylaxis has already been associated with the emergence and spread of resistant bacteria and strictly precludes the subsequent use of fluoroquinolones for initial empirical therapy; in addition, fluoroquinolones should be administered with caution among elderly patients, especially those with more pronounced vascular or degenerative impairment of the central nervous system, cardiac disease or electrolyte disturbances.

Novel Molecular Anti- Colorectalcancer Conjugate:Chlorambucil-Adipic Acid Dihydrizide-Glutamine by Maryam Akhavan Tabasi, Massoud Amanlou, Seyed Davar Siadat, Zahra Nourmohammadi, Farnoor Davachi Omoomi, Seyed Esmaeil Sadat Ebrahimi, Mohammad Reza Aghasadeghi, Pooneh Rahimi, Sahar Pourhosseini, Bita Mehravi, Mehdi Shafiee Ardestani (1449-1459).
Cancer is one of the most fatal diseases in the world and it has been years that finding new drugs and chemotherapeutic techniques with lowest side effects become one of the most important challenging matters needs really hard efforts. Chlorambucil (CBL), an ancient direct-acting alkylating anticancer agent, is commonly used for initial treatment of some kinds of cancers but the use of CBL is often limited because of the unpleasant side effects due to its lack of specificity for targeting cancer cells. In this research we tried to increase the specificity of CBL by producing a novel conjugate by using glutamine amino acid (Glut). Based on previous studies, poly amines and nitrogen compounds noticeably are used by cancer cells increasingly; therefore we decided to increase the efficiency and specificity of CBL by designing and producing a novel anti cancer conjugate using glutamine amino acid as an uptake enhancer, CBL, and Adipic acid Dihydrazide (ADH) as a spacer and linker. The biological tests were carried out on HT29 colorectal cancer cell line to evaluate its anticancer properties. Biological tests like MTT assay, finding IC50, evaluating the induced mechanism of the death of our novel CBL-Glutamine conjugate on HT29 cells, testing abnormal toxicity of this conjugate on mice in comparison with CBL drug were careid out. We found that not only CBL-Glutamine conjugate preserved its anti cancer property with regard to CBL drug, but also it represent lower abnormal toxicity in mice. Apoptosis was detected as its mechanism of the death. Our present study provides a promising strategy for targeting cancer cells using amino acids nano-conjugate drugs. The future perspectives have also been highlighted in continuing similar and relative researches.

Discovery of P3971 an Orally Efficacious Novel Anticancer Agent Targeting HIF-1α and STAT3 Pathways by Pallavi Godse, Pramod Kumar, Nilambari Yewalkar, Vijaykumar Deore, Manoj Lohar, Ramswaroop Mundada, Amol Padgaonkar, Sonal Manohar, Asavari Joshi, Dimple Bhatia, Nikesh Desai, Anagha Damre, Mandar Bhonde, Kalpana Joshi, Rajiv Sharma, Sanjay Kumar (1460-1466).
Hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) are transcription factors and are activated in response to hypoxia. Both HIF-1α and STAT3 regulate various aspects of cancer biology such as cell survival, proliferation, angiogenesis etc. and are constitutively expressed in a wide range of human cancers. In the last decade, over expression of HIF-1α and STAT3 has been demonstrated in many common human cancers, thereby emerging as highly compelling anticancer targets for drug discovery. We herein report the design and synthesis of new imidazopyridine based potent dual inhibitors of HIF-1α and STAT3 pathways. The lead compound of this series P3971 has been identified as a potent inhibitor of HIF-1α (200 nM) and STAT3 (350 nM) with significant antiproliferative activity against various cancer cell lines. Moreover, P3971 was also found to be orally efficacious in HCT116 (colon cancer) and H460 (lung cancer) xenograft mice models.