Pivoting Continuing Professional Development During the COVID-19 Pandemic: A Narrative Scoping Review of Adaptations and Innovations.

INTRODUCTION: Most formal continuing professional development (CPD) opportunities were offered in person until March 2020 when the COVID-19 pandemic disrupted traditional structures of CPD offerings. The authors explored the adaptations and innovations in CPD that were strengthened or newly created during the first 16 months of the pandemic. METHODS: The objectives of the narrative review were to answer the following questions: (1) what types of adaptations to CPD innovations are described? and (2) what may shape future innovations in CPD? The following databases were searched: Medline, Embase, CINAHL, and ERIC to identify the literature published between March 2020 to July 2021. The authors conducted a comprehensive search by including all study types that described adaptations and/or innovations in CPD during the stated pandemic period. RESULTS: Of the 8295 citations retrieved from databases, 191 satisfied the inclusion criteria. The authors found three categories to describe adaptations to CPD innovations: (1) creation of new online resources, (2) increased use of the existing online platforms/software to deliver CPD, and (3) use of simulation for teaching and learning. Reported advantages and disadvantages associated with these adaptations included logistical, interactional, and capacity building elements. The review identified five potential future CPD innovations: (1) empirical research on the effectiveness of virtual learning; (2) novel roles and ways of thinking; (3) learning from other disciplines beyond medicine; (4) formation of a global perspective; and (5) emerging wellness initiatives. DISCUSSION: This review provided an overview of the adaptations and innovations that may shape the future of CPD beyond the pandemic.

Evaluating the impact of continuing professional development courses on physician behavioral intention: a pre-post study with follow-up at six months.

BACKGROUND: Continuing professional development (CPD) for health professionals includes educational activities to maintain or improve skills. We evaluated the impact of a series of CPD courses by identifying factors influencing physicians' intention to adopt targeted behaviors and assessing self-reported behavior adoption six months later. METHODS: In this pre-post study, eligible participants attended at least one in-person course at the Fédération des Médecins Spécialistes du Québec annual meeting in November 2019. Before and afterwards, participants completed CPD-REACTION, a validated questionnaire based on Godin's integrated model for health professional behavior change that measures intention and psychosocial factors influencing intention. We used Wilcoxon signed-rank test to compare pre- and post-course intention scores and linear regression analyses to identify factors influencing intention. We also compared the post-course intention scores of participants reporting a behavior change six months later with the scores of those reporting no behavior change six months later. Qualitative data was collected only six months after courses and responses to open-ended questions were analyzed using the Theoretical Domains Framework. RESULTS: A total of 205/329 course attendees completed CPD-REACTION (response rate 62.3%). Among these participants, 158/329 (48%) completed the questionnaire before CPD courses, 129/329 (39.2%) only after courses and 47/329 (14.3%) at 6 months. Study population included 192 physicians of whom 78/192(40.6%) were female; 59/192(30.7%) were between 50 and 59 years old; and 72/192 (37.5%) were surgical specialist physicians. Mean intention scores before (n = 158) and after (n = 129) courses were 5.74(SD = 1.52) and 6.35(SD = 0.93) respectively. Differences in mean (DM) intention before and afterwards ranged from - 0.31(p = 0.17) to 2.25(p = 0.50). Multivariate analysis showed that beliefs about capabilities (ß = 0.15, p = 0.001), moral norm (ß = 0.75, p < 0.0001), and beliefs about consequences (ß = 0.11, p = 0.04) influenced post-course intention. Post-course intention was correlated with behavior six months later (DM = 0.63; p = 0.02). Qualitative analysis showed that facilitators to behavior adoption after six months were most often related to the TDF domains of beliefs about capabilities. Most frequent barriers to adoption related to lack of resources. CONCLUSIONS: Overall, scores for intention to adopt targeted behaviors increased after the courses. CPD providers could increase participants' intention by including interventions that emphasize beliefs about capabilities, moral norm and beliefs about consequences.

'We are in for a culture change': continuing professional development leaders' perspectives on COVID-19, burn-out and structural inequities.

INTRODUCTION: The COVID-19 pandemic positioned healthcare systems in North America at the epicentre of the crisis, placing inordinate stress on clinicians. Concurrently, discussions about structural racism, social justice and health inequities permeated the field of medicine, and society more broadly. The confluence of these phenomena required rapid action from continuing professional development (CPD) leaders to respond to emerging needs and challenges. METHODS: In this qualitative study, researchers conducted 23 virtual semistructured interviews with CPD leaders in Canada and the USA. Interview audiorecordings were transcribed, deidentified and thematically analysed. RESULTS: This study revealed that the CPD leaders attributed the pandemic as illuminating and exacerbating problems related to clinician wellness; equity, diversity and inclusion; and health inequities already prevalent in the healthcare system and within CPD. Analysis generated two themes: (1) From heroes to humans: the shifting view of clinicians and (2) Melding of crises: an opportunity for systemic change in CPD. DISCUSSION: The COVID-19 pandemic increased recognition of burn-out and health inequities creating momentum in the field to prioritise and restrategise to address these converging public health crises. There is an urgent need for CPD to move beyond mere discourse on these topics towards holistic and sustainable actionable measures.

Factors Associated With Specialists' Intention to Adopt New Behaviors After Taking Web-Based Continuing Professional Development Courses: Cross-sectional Study.

BACKGROUND: Web-based continuing professional development (CPD) is a convenient and low-cost way for physicians to update their knowledge. However, little is known about the factors that influence their intention to put this new knowledge into practice. OBJECTIVE: We aimed to identify sociocognitive factors associated with physicians' intention to adopt new behaviors as well as indications of Bloom's learning levels following their participation in 5 web-based CPD courses. METHODS: We performed a cross-sectional study of specialist physicians who had completed 1 of 5 web-based CPD courses offered by the Federation of Medical Specialists of Quebec. The participants then completed CPD-Reaction, a questionnaire based on Godin's integrated model for health professional behavior change and with evidence of validity that measures behavioral intention (dependent variable) and psychosocial factors influencing intention (n=4). We also assessed variables related to sociodemographics (n=5), course content (n=9), and course format (eg, graphic features and duration) (n=8). Content variables were derived from CanMEDS competencies, Bloom's learning levels, and Godin's integrated model. We conducted ANOVA single-factor analysis, calculated the intraclass correlation coefficient (ICC), and performed bivariate and multivariate analyses. RESULTS: A total of 400 physicians participated in the courses (range: 38-135 physicians per course). Average age was 50 (SD 12) years; 56% (n=223) were female, and 44% (n=177) were male. Among the 259 who completed CPD-Reaction, behavioral intention scores ranged from 5.37 (SD 1.17) to 6.60 (SD 0.88) out of 7 and differed significantly from one course to another (P<.001). The ICC indicated that 17% of the total variation in the outcome of interest, the behavioral intention of physicians, could be explained at the level of the CPD course (ICC=0.17). In bivariate analyses, social influences (P<.001), beliefs about capabilities (P<.001), moral norm (P<.001), beliefs about consequences (P<.001), and psychomotor learning (P=.04) were significantly correlated with physicians' intention to adopt new behaviors. Multivariate analysis showed the same factors, except for social influences and psychomotor learning, as significantly correlated with intention. CONCLUSIONS: We observed average to high behavioral intention scores after all 5 web-based courses, with some variations by course taken. Factors affecting physicians' intention were beliefs about their capabilities and about the consequences of adopting new clinical behaviors, as well as doubts about whether the new behavior aligned with their moral values. Our results will inform design of future web-based CPD courses to ensure they contribute to clinical behavior change.

Use of the CPD-REACTION Questionnaire to Evaluate Continuing Professional Development Activities for Health Professionals: Systematic Review.

BACKGROUND: Continuing professional development (CPD) is essential for physicians to maintain and enhance their knowledge, competence, skills, and performance. Web-based CPD plays an essential role. However, validated theory-informed measures of their impact are lacking. The CPD-REACTION questionnaire is a validated theory-informed tool that evaluates the impact of CPD activities on clinicians' behavioral intentions. OBJECTIVE: We aimed to review the use of the CPD-REACTION questionnaire, which measures the impact of CPD activities on health professionals' intentions to change clinical behavior. We examined CPD activity characteristics, ranges of intention, mean scores, score distributions, and psychometric properties. METHODS: We conducted a systematic review informed by the Cochrane review methodology. We searched 8 databases from January 1, 2014, to April 20, 2021. Gray literature was identified using Google Scholar and Research Gate. Eligibility criteria included all health care professionals, any study design, and participants' completion of the CPD-REACTION questionnaire either before, after, or before and after a CPD activity. Study selection, data extraction, and study quality evaluation were independently performed by 2 reviewers. We extracted data on characteristics of studies, the CPD activity (eg, targeted clinical behavior and format), and CPD-REACTION use. We used the Mixed Methods Appraisal Tool to evaluate the methodological quality of the studies. Data extracted were analyzed using descriptive statistics and the Student t test (2-tailed) for bivariate analysis. The results are presented as a narrative synthesis reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Overall, 65 citations were eligible and referred to 52 primary studies. The number of primary studies reporting the use of CPD-REACTION has increased continuously since 2014 from 1 to 16 publications per year (2021). It is available in English, French, Spanish, and Dutch. Most of the studies were conducted in Canada (30/52, 58%). Furthermore, 40 different clinical behaviors were identified. The most common CPD format was e-learning (34/52, 65%). The original version of the CPD-REACTION questionnaire was used in 31 of 52 studies, and an adapted version in 18 of 52 studies. In addition, 31% (16/52) of the studies measured both the pre- and postintervention scores. In 22 studies, CPD providers were university-based. Most studies targeted interprofessional groups of health professionals (31/52, 60%). CONCLUSIONS: The use of CPD-REACTION has increased rapidly and across a wide range of clinical behaviors and formats, including a web-based format. Further research should investigate the most effective way to adapt the CPD-REACTION questionnaire to a variety of clinical behaviors and contexts. TRIAL REGISTRATION: PROSPERO CRD42018116492; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=116492.

Rethinking Our Annual Congress-Meeting the Needs of Specialist Physicians by Partnering With Provincial Simulation Centers.

ABSTRACT: Canada's maintenance of certification programs for physicians has evolved to emphasize assessment activities. Our organization recognized the importance of offering more practice assessment opportunities to our members to enhance their practice and help them comply with a regulation from our provincial professional body related to ongoing continuing education. This led us to rethink our annual congress and enrich the program with a curriculum of interdisciplinary simulation sessions tailored to meet the needs of a broad audience of specialists. Our challenges are similar to those of many national specialty societies having limited access to simulation facilities, instructors, and simulation teams that can cover the breadth and scope of perceived and unperceived simulation needs for their specialty. Our innovative solution was to partner with local experts to develop 22 simulation sessions over the past three years. The response was very positive, drawing 867 participants. Over 95% of participants either agreed or strongly agreed that their simulation session (1) met their learning objectives, (2) was relevant for their practice, and (3) encouraged them to modify their practice. Narrative comments from a survey sent to the 2018 participants four months after their activity indicated several self-reported changes in their practice or patient outcomes. We were able to centralize offers from organizations that had previously worked in silo to develop simulation sessions meeting the needs of our members. Proposing simulation sessions allowed our organization to establish long-term partnerships and to expend our "educational toolbox" to address skill gaps not usually addressed during annual meetings.

Implementation of Interdisciplinary Province-Wide Webinar Series During the COVID-19 Pandemic by the Federation of Medical Specialists of Quebec (FMSQ): A Survey Study.

Objectives: COVID-19 has forced a transformation in continuing professional development (CPD), shifting to virtual platforms. We report the results of a rapidly-implemented COVID-19 online interdisciplinary CPD webinar series. We aimed to determine if this virtual approach for large-scale CPD was relevant, appreciated, and effective for specialist physicians in Quebec. Methods and Analysis: This was a retrospective descriptive online survey-based study. The weekly virtual educational webinars took place between March 3, 2020 to June 15, 2020, resulting in a total of 26 webinars over 16 weeks. The study included all individuals who attended any of the webinar sessions, namely specialist physicians and department chiefs. Number of participants and overall appreciation of webinar sessions were data points collected. Results: Across all webinars, there were 8,500 unique specialist physicians which comprises 80.7% of the entire specialist practicing population in Quebec. Of note, every medical and surgical specialty was represented by attendance in at least one session. In total, 27,504 evaluation forms were completed out of all the sessions, meaning a 78.4% response rate. In post-webinar surveys, 97.6% of respondents agreed or strongly agreed that the webinars were pertinent to their practice and 94.6% agreed or strongly agreed that the presentation met their continuing professional needs. Conclusions: This novel interdisciplinary COVID-19 webinar series is a successful and appreciated strategy to maintain CPD amidst a global pandemic. One year later, it has become a mainstay in our toolbox and we trust this unique model of large-scale interdisciplinary CPD via webinar sessions is useful in normal times as well as in times of crisis.

Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme.

Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.

Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R.

Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: in vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.

Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.

Nazarov reactions of vinyl cyclopropylamines: an approach to the imino-Nazarov problem.

Dichlorocyclopropanation of 2-amino-1,3-dienes affords 1-alkenyl-1-amino-2,2-dichlorocyclopropanes which undergo silver-assisted 2-π electrocyclic opening to furnish 3-aminopentadienyl cations. Nazarov-type cyclization of these intermediates leads to cyclopentenone iminium salts, which provide allylic amines upon reduction. This process, the imino version of the traditional Nazarov reaction, can also be combined with an interrupted Nazarov domino process to give polycyclic amines.

Nucleotide competing reverse transcriptase inhibitors: discovery of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.

A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.

The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway.

1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. IPI-926 is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926 is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, IPI-926 has desirable pre-clinical absorption, distribution, metabolism and excretion properties.

Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors.

Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.

Inhibition of HIV-1 capsid assembly: optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold.

A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H-benzimidazole series that inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the antiviral potency by a . The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification of major interactions between the inhibitor and the protein.

Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.

Mapping human dimensions of climate change research in the Canadian Arctic.

This study maps current understanding and research trends on the human dimensions of climate change (HDCC) in the eastern and central Canadian Arctic. Developing a systematic literature review methodology, 117 peer reviewed articles are identified and examined using quantitative and qualitative methods. The research highlights the rapid expansion of HDCC studies over the last decade. Early scholarship was dominated by work documenting Inuit observations of climate change, with research employing vulnerability concepts and terminology now common. Adaptation studies which seek to identify and evaluate opportunities to reduce vulnerability to climate change and take advantage of new opportunities remain in their infancy. Over the last 5 years there has been an increase social science-led research, with many studies employing key principles of community-based research. We currently have baseline understanding of climate change impacts, adaptation, and vulnerability in the region, but key gaps are evident. Future research needs to target significant geographic disparities in understanding, consider risks and opportunities posed by climate change outside of the subsistence hunting sector, complement case study research with regional analyses, and focus on identifying and characterizing sustainable and feasible adaptation interventions.

Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein.

The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV-1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action.

New developments in the discovery of small molecule Hedgehog pathway antagonists.

The Hedgehog (Hh) signaling pathway is crucial for normal embryonic development. Aberrant Hh signaling is implicated in numerous pathologic conditions including proliferative diseases such as cancer. During the past decade, academic and industrial research efforts have resulted in the discovery of a variety of Hh pathway antagonists. This review focuses on the most recent advances in this field with particular emphasis on the medicinal chemistry approaches used to discover these Hh antagonists. While most of the small molecule modulators of the Hh pathway were discovered through screening and subsequent medicinal chemistry, a number of them originated from rational design or natural products.