The Supremacy Clause only applies to laws that are consistent with the US Constitution.
The Interstate Commerce clause is intended to improve trade between the states. It is not an all encompassing authority to regulate business.
The General Welfare clause exists as opposed to specific welfare. It would be improper to tax all for the benefit of a few. General Welfare is not blanket power to do anything that is 'good'.
The Federal Government does not have blanket authority to spend on anything.
Almost all government departments lack the Constitutional Authority to exist.
The Constitution of the United States exists primarily as a limitation of Federal Government power. It must be followed, every issue... every time.