Despite scientific advances in understanding the causes and treatment of human malignancy, a persistent challenge facing basic and clinical investigators is how to adequately treat primary and metastatic brain tumors. The blood-brain barrier is a physiologic obstruction to the delivery of systemic chemotherapy to the brain parenchyma and central nervous system (CNS). (Deeken et. al., Clin Cancer Res 2007; 13(6) 2007, 1663-1674). Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking (Muldoon et. al. J Clin Oncol. 2007, 25(16):2295-305. Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. (Ohgaki et. al. American Journal of Pathology, 170(5), 2007, 1445-1453). Thus, there remains a need to develop treatments for brain related disorders that can cross the blood brain barrier.
Patients with secondary brain tumors also have poor treatment prognosis due to the difficulty in delivering drugs across the blood brain barrier. Metastatic brain tumors are the most common intracranial neoplasm in adults, and although the exact incidence is unknown, it has been estimated to be as high as 200,000 cases per year in the U.S. alone. The frequency of metastatic brain tumors appears to be rising as a result of superior imaging modalities and earlier detection as well as longer survival after a primary cancer diagnosis because of more effective treatment of systemic disease. (Eichler et. al. The Oncologist, 12 (7), 884-898, 2007).
Patients with lung cancer account for approximately 50% of brain metastasis cases. The majority of active cytotoxic agents (like taxanes) in lung cancer treatment, are unable to effectively penetrate blood brain barrier (BBB). (Zarogoulidis et. al., Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I, 24(18S) 2006. Considering the challenge in BBB penetration and the brain metastasis of lung cancer anti-cancer agents that can highly distribute to lung and cross blood brain barriers are highly sought after in cancer treatment of brain cancer and lung cancer with brain metastasis.
HSP90s are ubiquitous chaperone proteins that are involved in proper protein folding and stabilization of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2, many of which are overexpressed or mutated in various cancers (Buchner J. TIBS, 1999, 24, 136 141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491 502; Dai, K. et al. J. Biol. Chem. 1996, 271, 22030-4). Studies further indicate that certain co-chaperones, e.g., HSP70, p60/Hop/Stil, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in its function (Caplan, A. Trends in Cell Biol. 1999, 9, 262 68). HSP90 is overexpressed in many cancers and has become a target for cancer therapy. HSP90 inhibitors possess potent anti-proliferative activity, usually at low nanomolar ranges, owing to their pharmacological characteristics of binding tightly to heat shock protein 90, coupled with a slow dissociation rate. (Newcomb et. al. Anticancer Drugs 2007 18(8):875-82). HSP90 has been shown to be present in a variety of primary and metastatic intracranial tumors including glioblastomas and medulloblastomas (Kato et. al., Acta Neuropathol. 1995; 89(2):184-8).
Recent studies also suggest that heat shock proteins (HSPs) play an important role in neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotropic lateral sclerosis (ALS), Huntington disease (HD) (Luo, G-R. Int. J. Biol. Sci., 2007, 3(1), 20-26; Dickey, C., J. Clin. Invest., 2007, 117(3), p. 648-658). It has been shown that manipulation of HSPs, such as down regulation of HSP90 or up regulation of HSP70, affords beneficial effects in several neurodegenerative disorders either by reducing protein aggregation or facilitating proper folding of proteins to restore their function. Neurodegenerative diseases such as Alzheimer's disease (AD) and Huntington's disease (polyglutamine disease) are typical diseases likely caused by the abnormal accumulation of misfolded and aggregated proteins, and these diseases are thought to be inhibited by the action of Hsp70 as a chaperone. Apoptosis is one of the ways neurons die after ischemia. It has been shown that overexpression of Hsp70 in hippocampal CA1 neurons reduces evidence of protein aggregation under conditions where neuronal survival is increased (Giffard, R. G., et al., J. Exp. Biol. 207:3213-3220 (2004)).
A growing body of evidence supports the hypothesis that HSP90 inhibition affords neuroprotection in various animal models of neurological disease. HSP90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells. However, HSP90 is overexpressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of HSP90 than normal cells. For example, cancer cells typically have a large number of mutated and over expressed oncoproteins that are dependent on HSP90 for folding. In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on HSP90 for survival. Moreover, inhibition of HSP90 causes simultaneous inhibition of a number of client oncoproteins, as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent. In fact, benzoquinone ansamycins, a family of natural products that inhibit HSP90, has shown evidence of therapeutic activity in clinical trials. Several promising ansamycin related HSP90 inhibitors are currently in clinical trial namely, 17-allylamino 17-demethoxygeldanamycin (17-AAG), 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and IPI-504. Another class of the HSP90 inhibitor is the synthetic small molecule purine-scaffold. Currently, many of the purine-scaffold HSP90 inhibitors are showing positive preclinical results; with the front runner being CNF-2024, which is currently in phase 1 clinical trial.
In recent years, molecularly targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors, have gained tremendous attention for their potential to improve patient survival and reduce toxic side effects, in particular for the treatment of lung cancer. Yet, early clinical trials of these inhibitors, such as gefitinib and erlotinib, were modestly encouraging, with a response in only ˜10% of patients who carry genetic mutations of EGFR (Bao et. al., Mol. Cancer. Ther. 2009; 8(12) 2009). In addition, resistance almost invariably develops in these non-small cell lung cancer (NSCLC) patients although they respond to these receptor tyrosine kinase (RTK) inhibitors initially. Of these instances of so-called “acquired” resistance, it is estimated that ˜50% are due to the emergence of an additional EGFR mutation in exon 20 (EGFRT790M), the “gatekeeper” residue within the kinase domain (Kobayashi et. al., N. Engl. J. Med. 2005; 352: 786-92; Proc. Natl. Acad. Sci. 2005, 102 11011-6). Structural analysis suggests that the T790M mutation sterically hinders the binding of erlotinib to the EGFR kinase domain by introducing a bulky methionine residue, thereby conferring erlotinib resistance (8, 9). There is also evidence to suggest that T790M mutation causes drug resistance by increasing the affinity of EGFR for ATP (Yun et. al., Proc. Natl. Acad. Sci. 2008, 105, 2070-5). To overcome such EGFRT790M-mediated resistance, several irreversible EGFR inhibitors able to form covalent bonds with Cys-797 at the edge of the ATP binding site are actively being tested in clinical trials. However, only modest efficacy has been reported, believed to be in part due to persistent PI3K/AKT/mTOR signaling following treatment (Bao et. al.).
Drugs targeting the protein HSP90 are quite new in cancer and neurodegenerative disease therapies. Their presence in many of the tumors associated with CNS point to a need for HSP-related drugs capable of crossing the blood brain barrier. As such, a promising therapy for brain related disorders would be HSP90 inhibitors that are efficient in crossing the blood brain barrier. This invention relates to fused amino pyridine compounds useful as HSP90 inhibitors for the treatment of brain related disorders. This invention further relates to treatment of cancers that are resistant to other epidermal growth factor receptor inhibitors. This invention further relates to the inhibition of HSP70 and the treatment of diseases related to HSP70.