Nicholas K. Email & Phone Number

Cambridge, England, Gb

Led chemistry efforts on multiple immuno-oncology programs, leveraging Bicycle technology to design and develop potent, selective agonists. Optimized compounds through non-natural amino acid substitution, achieving sub-nanomolar KD values with favorable pharmacokinetic properties. Created targeted agonists for homo-multimeric and heterodimeric receptors, resulting in picomolar EC50s in primary and engineered reporter cell assays. Collaborated across teams to identify binding epitopes and determine structure-activity relationships, leading to the design and validation of first-in-class targeted heterodimeric receptor agonists. Utilized phage display data on identified bicyclic monomers to inform design strategies and compound optimization. Addressed solubility and stability issues in advanced molecules and coordinated scale-up for in vitro validation of demonstrated agonism. Managed relationships with multiple functional divisions within Bicycle Therapeutics and with CROs internationally, ensuring efficient project progression. Delivered monthly and quarterly updates to VPs and senior management at a large pharmaceutical collaborator, effectively communicating complex scientific data and project milestones. Championed improvements to the internal data platform, enhancing compound registration and experimental result visualization.

Cambridge, Ma, Us

Drove synthesis and development of phosphorodiamidate morpholino oligomers (PMOs) to enhance intracellular delivery and modify biological activity. Led program development of non-viral delivery approaches, involving solid-phase synthesis, peptide conjugation, and novel moiety design. Coordinated in vivo/in vitro studies to test and iterate on these novel delivery systems. Managed both internal programs and joint development initiatives with collaborators, focusing on advancing oligonucleotide-based therapeutics for rare diseases.

Cambridge, Ma, Us

Contributed to the development and optimization of oligonucleotide therapeutics for rare diseases. Conducted solid-phase synthesis and modulation of PMOs, designed modifications to optimize delivery and nuclear localization. Utilized various analytical techniques, including Isothermal Titration Calorimetry, to assess binding affinities and conjugation effectiveness.

Brentford, Middlesex, Gb

Designed, synthesized, purified, and analyzed small molecules selectively targeting kinases to control immune system response. Focused on modulating pharmacokinetic properties while identifying SAR trends contributing to selectivity, permeability, stability, and potency in biochemical & cellular binding assays. Leveraged crystallographic data, molecular modeling, and synthetic literature to optimize routes, delivering compounds on milligram to multi-gram scales for in vivo PK studies and formulations. Presented work in internal project meetings and company-wide poster presentations. Provided synthetic troubleshooting support to CRO chemists, managed ongoing synthesis, and performed data interpretation & validation. Led upkeep and training on analytical & prep-scale high pressure chromatographic instruments, assisted in safety compliance, and oversaw maintenance of organic synthesis lab instruments.

Us

Spinal Muscular Atrophy is the leading cause of genetic infant mortality and is characterized by the degeneration of motor neurons. One target for therapy involves up-regulation of the survival motor neuron (SMN) protein by increasing the amount of SMN2 mRNA. To achieve this, a library of small molecules has been designed and synthesized based on a scaffold discovered in a high throughput screen. From this, 51 final compounds were tested in SMN luciferase assays developed by a collaborator at Indiana University to determine increases in SMN protein levels by determining SMN2 mRNA increase. Of these compounds, one lead was selected for a mouse PK study and six other molecules were selected for further plasma stability testing. These compounds, as well as several others, were found to increase EC50 as well as SMN2 availability compared to the previous lead compound and have given way to a more robust understanding of the structure based activity of the molecules.

Boston, Ma, Us

A novel approach to the production of heterocycles has been developed. Continuous flow microreactor technology was utilized to beget azides in situ and thereupon react them with cyanoacetamide in a [3+2] cycloaddition in order to yield a library of practical triazole components. Given concerns about the use of organic azides in macroscale synthesis, flow chemistry provides a safe method of reacting intermediates in a scalable manner while controlling strong thermodynamic properties. This methodology is favorable due to the greater surface-to-volume ratio of heating reactions in flow, as well as laminar flow mixing. Together, these help diminish the risks of hazardous side reactions while allowing for more efficient synthesis. As a result a library of triazole scaffolds was created in a safe, efficient, and scalable method, allowing for easier availability of desirable building blocks.

Rahway, New Jersey, Us

An approach to protecting primary amines was developed through introduction of pyrroles via Paal-Knorr synthesis. The primary amines were cyclized with 1,4-diketones to produce pyrroles of varying substitution, acting as unique protective groups at isolated yields above 97%. These pyrroles showed unique properties as a protecting group to that of a tert-Butyloxycarbonyl or Carbobenzyloxy protection group and allowed for the possibility of selective reactivity of amines on the scaffold. Methods of deprotection involving hydroxylamine were also developed resulting in isolation of the HCl salt of the primary amine.

Cambridge, Ma, Us

Methods to synthesis of a lead oncology compound were developed utilizing meso-scale continuous flow technology optimized to allow reagent and cost efficiency. This methodology allowed for unique control of kinetics and temperature in a scalable, reproducible manner. Alongside this project, novel methods of sulfamoyl substitution were performed on small molecules. These syntheses were performed on up to 1.6 gram scale resulting in sixteen pure isolated final compounds at yields from 70%-90%. I performed routine upkeep on the Vapourtec R2 flow system and assisted employees on flow integration of projects when applicable.

Basel, Baselstadt, Ch

Macular degeneration is a disease common in older adults, affecting the retina where the focus of treatment has been in inhibiting an enzyme believed to be involved in the disease. To achieve this inhibition, a variety of substitutions on the phenyl ring of a lead compound was explored. These substitutions altered several characteristics of the molecule including steric bulk, electronic properties, and cLogP, with the overall goal to improve potency, selectivity, and permeability. 2-Aminophenylacetic acid building blocks with differing substitution patterns were prepared using a variety of synthetic pathways. These intermediates were then coupled to the other half of the molecule to make amide-linked final compounds. Seventeen final compounds were made on a 10-30 mg scale, including one compound which showed enhanced permeability and was selected for an in vivo PK study.

Master Of Science (M.S.), Chemistry

Bachelor Of Science (B.S.), Chemistry

Education record