Development of Potent and non-toxic rexinoids to prevent non-melanoma skin cancer

摘要： 非黑色素瘤皮肤癌（NMSC），包括基底细胞癌（BCC）和鳞状细胞癌 (SCC)是美国最常见的癌症类型之一。由于免疫力下降，实体器官 移植受者（SOTR）患NMSC的风险要高得多，并且它经常成为死亡的原因。 SOTR。预防NMSC是一种理想的策略，特别是对于免疫受损的人群。Rexinoids 是小分子药物，能够预防皮肤癌。然而，一些不利影响可能会导致 在使用中不遵守。我们已经开发了两种不同类型的rexinoids结构：UAB 30和 UAB 20，其为高度选择性、无毒且口服生物可利用的RXR激动剂。这些代理商也高度 有效预防皮肤癌，正如我们的初步数据所示。UAB 30和UAB 20都不会导致 高脂血症，通常与临床批准的rexinoids相关的作用。与癌症相关的 炎性生物标志物也是这些试剂的吸引人的特性。因此，我们的热情， 开发这些药剂的高效类似物作为癌症化学预防剂促使我们 提交这个提案。在X射线晶体学和生物物理学研究的指导下，我们提出开发新的 具有比母体化合物增强的效力的UAB 30和UAB 20的类似物， 长期给药且无任何明显毒性。UAB 30的低能分子构象符合 RXR配体结合口袋（LBP）。我们的策略是在不扭曲 这两种药物的分子构象。因此，我们建议用 卤素和/或杂原子。由于氟的电负性和碳氟的强度 邦德，我们已经推断，氟的战略引入将提高效力，口服生物利用度， 新合成的类似物的代谢稳定性和药代动力学。杂原子如氮可以 显著调节极性（logP）值。因此，我们建议用一个碳原子取代 UAB 30的四氢萘酮环上带有一个氮。单独和集体地，这些修改将显著地 有助于UAB 30类似物的效力，并将使其成为临床前评估的理想试剂。同样地， 对于UAB 20，X射线晶体结构显示，五元杂环被容纳更多， 有利地并在LBP内进行互动。因此，我们建议用以下取代苯环： 杂环。这些修饰还将调节IogP并改善这些新的化合物的药代动力学。 类似物我们在该应用中的合作研究者已经开发了独特的NMSC小鼠模型， 概括了正常人群和SOTR中疾病的人类病理学。这些模型将在 在拟议的研究中使用，以确定最有效和无毒的类似物，适用于慢性 施用用于NMSC化学预防。在此期间，我们希望开发至少一个新的 在GLP毒性评估后，rexinoid准备进行临床开发。

Abstract: Non-melanoma skin cancer (NMSC), which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is one of the most common types of cancers in the US. Due to compromised immunity, solid organ transplant recipients (SOTRs) are at a much higher risk for NMSC and it often becomes the cause of death in SOTRs. Prevention of NMSC is an ideal strategy, particularly for immune compromised populations. Rexinoids are small molecule drugs and are able to prevent skin cancer. However, some of the adverse effects may lead to non-compliance in their use. We have developed two distinct classes of structures of rexinoids: UAB30 and UAB20, which are highly selective, non-toxic and orally bioavailable RXR agonists. These agents are also highly effective in preventing skin cancer as shown in our preliminary data. Both UAB30 and UAB20 do not cause hyperlipidemia, an effect usually associated with clinically approved rexinoids. Dampening cancer associated inflammatory biomarkers is also an attractive property of these agents. Thus, our enthusiasm for further developing highly effective analogs of these agents as cancer chemopreventive agents has prompted us to submit this proposal. Guided by x-ray crystallography and biophysical studies, we propose to develop novel analogs of UAB30 & UAB20 with enhanced potency than parent compounds, with suitable pharmacokinetics for chronic administration and without any overt toxicity. Low energy molecular conformation of UAB30 fit well into the RXR ligand-binding pocket (LBP). Our strategy is to improve the potency significantly without distorting the molecular conformations of these two agents. Therefore, we propose to substitute a hydrogen atom with a halogen and/or a heteroatom. Because of the electronegativity of fluorine and the strength of carbon-fluorine bond, we have reasoned that strategic introduction of fluorine will improve the potency, oral bioavailability, metabolic stability and pharmacokinetics of the newly synthesized analogs. Heteroatoms such as nitrogen can modulate the polarity (logP) value significantly. Therefore, we have proposed to substitute a single carbon of tetralone ring of the UAB30 with a nitrogen. Individually and collectively, these modifications will significantly contribute to the potency of UAB30 analogs and will make them ideal agents for pre-clinical evaluation. Similarly, for UAB20, x-ray crystal structures reveal that a five membered heterocyclic ring is accommodated more favorably and make interactions within the LBP. Therefore, we have proposed to substitute the phenyl ring with heterocyclic rings. These modifications will also modulate the logP and improve pharmacokinetics of these new analogs. Our co-investigator in this application has developed unique murine models of the NMSC, which recapitulate human pathobiology of the disease both in normal population and in SOTRs. These models will be employed in the proposed investigations to define the most effective and non-toxic analogs suitable for chronic administration for NMSC chemoprevention. During this grant period, we expect to develop at least one new rexinoid ready for clinical development after GLP toxicity evaluation.